Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3]/[C:2]/1=[CH:6]/[S:7]([N:10]1[CH2:31][CH2:30][C:13]2([C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:12][CH2:11]1)(=[O:9])=[O:8]>CO>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][S:7]([N:10]1[CH2:11][CH2:12][C:13]2([C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:30][CH2:31]1)(=[O:9])=[O:8]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)/C=C1/CCCO1)CC2
Solvent: CO
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC1CCCO1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
8-[Dihydro-furan-(2Z)-ylidenemethanesulfonyl]-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 213, 15 mg, 0.03 mmol) was dissolved in MeOH (2 mL). The flask was evacuated and then purged with argon. Pd/C (2 mg) was added in one portion and the flask was evacuated, then purged with hydrogen three times. The reaction mixture was then stirred at room temperature for 16 h. The mixture was filtered through Celite® and the filtrate was then concentrated in vacuo and purified by flash column chromatography (3:2 AcOEt/heptane) to give 8-(tetrahydro-furan-2-ylmethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (5 mg, 33%) as a white solid. MS (ESI): 463.3 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16].C(OCC)(=O)C>CS(C)=O>[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][NH:12][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCC(O)CO
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1NCC(O)CO
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a stirred solution of 2,4-difluoronitrobenzene (3.18 g., 20 mmole) in DMSO (10 ml) was added portion-wise a solution of 3-amino-1,2-propanediol (3.64 g., 40 mmole) in DMSO (5 ml) in an ice bath. The mixture was stirred at 23° C. for 30 min. and poured into crushed ice. After addition of ethyl acetate, the organic layer was separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure to give the compound (18) (3.6 g., 78%) as a yellow solid.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([NH2:18])(=[O:17])[CH:15]=[CH2:16].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:5][C:3]([CH:2]1[CH2:16][CH2:15][C:14](=[O:17])[NH:18][C:1]1=[O:9])=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(=O)NC1=O
Reaction time: 0.17 h

Procedure:
To a solution of diethyl malonate (2.3 ml) in tetrahydrofuran (2.3 ml) cooled at 0° C. is added sodium hydride (400 mg). After stirring for 10 minutes, the mixture is mixed with acrylamide (710 mg) and let react at 0° C. for 70 minutes and at room temperature for 3.5 hours. The mixture is mixed with acetic acid (0.7 ml), stirred for 20 minutes, diluted with ethyl acetate, filtered to remove solid, concentrated, and triturated in n-hexane to afford 2,6-dioxo-piperidine-3-carboxylic acid ethyl ester (1.18 g). m.p. 69°-74° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([CH3:33])[N:26]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:6]1[CH:5]=[C:4]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([CH3:33])[N:26]=2)[C:3]([C:1]#[N:2])=[N:8][CH:7]=1
Reactant: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)ccc1C#N
Reaction time: 16 h

Procedure:
To a solution of tert-butyl [(1S,2R)-2-({6-cyano-5-[(5-cyano-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate (58 mg, 0.13 mmol) in dichloromethane (1.3 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol) at room temperature. After 16 hours, the reaction mixture was concentrated under reduced pressure to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(5-cyano-6-methylpyridin-2-yl)amino]pyridine-2-carbonitrile. The material was used in the next step without further purification. MS ESI calc'd for C19H22N7 [M+H]+ 348. found 348.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:36][C:37](Br)=[CH:38][CH:39]=1)(=[O:34])=[O:33])[CH2:29][OH:30]>>[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:38][CH:39]=1)(=[O:34])=[O:33])[CH2:29][OH:30]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=S(=O)(NC(CO)CO)c1ccc(Br)s1
Product: O=S(=O)(NC(CO)CO)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.54) (158 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (117 mg, 40%). MS (ISN) 589.3 [(M−H)−]; mp 210° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([F:28])=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(F)c3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 103.8 %

Procedure:
The mixture of 2-[(4-fluoro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (43) (180 mg, 0.48 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 6 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (44) as white solid (174 mg, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20](OC)=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl.Cl.CN(C)CCO[C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[NH2:7][CH:6]1[CH2:8][C:41]2[CH:42]=[C:43]([NH:44][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:22]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:20]=[CH:19][CH:18]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:45]=[CH:46][C:47]=2[CH2:4][CH2:5]1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Agent: Cl
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 64.4 %

Procedure:
N-[5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2-(2-thienyl)acetamide (119 mg, 0.25 mmol) and 3-{[2-(dimethylamino)ethyl]oxy}-aniline dihydrochloride (127 mg, 0.50 mmol) were coupled according to the procedure of Example 56, Step H to give the title compound (46 mg, 30%). 1H NMR (400 MHz, d6-DMSO) δ 8.80 (s, 1H), 8.48 (d, J=7.2 Hz, 1H), 8.35 (d, J=9.2 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.49 (s, 1H), 7.28-7.24 (m, 4H), 7.22-7.18 (m, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.04-7.03 (m, 2H), 6.89-6.86 (m, 2H), 6.61-6.59 (m, 2H), 4.09 (m, 2H), 3.95 (s, 2H), 3.81 (s, 3H), 2.76 (m, 2H), 2.35 (s, 6H) ppm. ES-LC/MS m/z=620 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][O:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C(Cl)Cl>C1(C)C=CC=CC=1>[C:11]1([C:10]2[C:6]([CH2:4][OH:3])=[CH:7][O:8][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cocc1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1cocc1-c1ccccc1
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Prepare a solution of 4-phenylfuran-3-carboxylic acid ethyl ester (3.9 g, 18.1 mmol) in toluene (20 mL) under nitrogen at −78° C. Add a 1.0 M solution of Diisobutyl aluminium hydride in methylene chloride (35 mL, 35.0 mmol). Stir the reaction mixture for 1 hour, quench with water, and pour into 10% Rochelle's salt (200 mL). Extract the aqueous phase with ethyl acetate (2×200 mL). Wash the organic phase with brine (100 mL), dry (Na2SO4), filter, and concentrate. Flash chromatography on silica gel eluting with 4:1 Hex/ethyl acetate to afford 2.3 g of (4-phenylfuran-3-yl)methanol. 1H NMR (CDCl3) δ 7.51-7.58 (m, 4H), 7.30-7.45 (m, 3H), 4.67 (d, J=5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1>[I-].[K+].C(O)(C)C>[CH3:36][C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][N:13]2[CH2:12][CH2:11][CH:10]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:9])[CH2:15][CH2:14]2)=[CH:33][CH:32]=1)([CH3:35])[CH3:37]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)c1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 41 %

Procedure:
Following the procedure of Example 1, α,α-bis (p-fluorophenyl)-4-piperidinemethanol and 4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give with white powder (recrystallizing from isopropyl alcohol) in 41% yield, m.p. 126°-127° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][N:6]1[CH2:14][CH:13]2[CH:8]([CH:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH2:12]2)[CH2:7]1.[OH-].[Na+].C1(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=O)C=2C=CC=1>Cl>[C:19]1([CH:9]2[CH:8]3[CH:13]([CH2:14][N:6]([CH2:5][CH2:4][C:3]([OH:25])=[O:2])[CH2:7]3)[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]2=3)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCN1CC2Cc3ccccc3C(c3ccccc3)C2C1
Agent: Cl
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: [Na+]
Product: O=C(O)CCN1CC2Cc3ccccc3C(c3ccccc3)C2C1

Procedure:
10 g of (3aRS,4SR,9aSR)-3a,4,9,9a-tetrahydro-4-phenyl-benz[f]isoindoline-2-propionic acid methyl ester are heated to the boil at reflux in 50 cc of 2 N hydrochloric acid for 5 hours. The solution is then concentrated by evaporation, the residue is dissolved in water, the pH of the solution is adjusted to 1 with caustic soda solution, and 1 equivalent of 1,5-naphthalene disulphonic acid is added, whereby the bis-1,5-naphthalene-disulphonate salt form of the title compound is obtained in sticky form. The supernatant water is poured off and the resin is triturated with acetone, whereby it crystallizes. M.P. 193°-195°.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CCP(=O)OCCCN4C=C(B5OC(C)(C)C(C)(C)O5)C=N4)=CC=3OC)N=2)=CC=1.[Br:54][C:55]1[N:60]=[C:59]([C:61](=[O:64])[NH:62][CH3:63])[C:58]([NH:65][C:66]2[C:71]([C:72]([F:75])([F:74])[F:73])=[CH:70][N:69]=[C:68]([NH:76][C:77]3[CH:87]=[CH:86][C:80]([CH2:81][CH2:82][PH:83](=[O:85])[OH:84])=[CH:79][C:78]=3[O:88][CH3:89])[N:67]=2)=[CH:57][CH:56]=1.[CH3:90][C:91]([CH3:109])([CH2:94][N:95]1[CH:99]=[C:98]([B:100]2[O:104][C:103]([CH3:106])([CH3:105])[C:102]([CH3:108])([CH3:107])[O:101]2)[CH:97]=[N:96]1)[CH2:92]O>>[Br:54][C:55]1[N:60]=[C:59]([C:61](=[O:64])[NH:62][CH3:63])[C:58]([NH:65][C:66]2[C:71]([C:72]([F:75])([F:73])[F:74])=[CH:70][N:69]=[C:68]([NH:76][C:77]3[CH:87]=[CH:86][C:80]([CH2:81][CH2:82][PH:83](=[O:84])[O:85][CH2:90][C:91]([CH3:109])([CH3:92])[CH2:94][N:95]4[CH:99]=[C:98]([B:100]5[O:104][C:103]([CH3:106])([CH3:105])[C:102]([CH3:108])([CH3:107])[O:101]5)[CH:97]=[N:96]4)=[CH:79][C:78]=3[O:88][CH3:89])[N:67]=2)=[CH:57][CH:56]=1
Reactant: CC(C)(CO)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Agent: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Yield: 19.6 %

Procedure:
This material was prepared analogously to Compound 61A using (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)methylphosphinic acid (Compound 61B, 250 mg, 0.42 mmol) and 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 47B, 119 mg, 0.424 mmol) to afford 70 mg of the title compound (19%). MS (ESI): m/z=851.22/853.23 [M+H]+. UPLC: tR=1.17 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][CH:8]([F:14])[C:9](OCC)=[O:10])([CH3:6])=[O:5])[CH3:2].[OH-].[NH4+:16]>C(O)C>[NH2:16][C:9](=[O:10])[CH:8]([F:14])[CH2:7][P:4]([CH3:6])(=[O:5])[O:3][CH2:1][CH3:2]
Reactant: CCOC(=O)C(F)CP(C)(=O)OCC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(C)(=O)CC(F)C(N)=O
Yield: 86.7 %

Procedure:
A solution of ethyl 3-[ethoxy(methyl)phosphoryl]-2-fluoropropanoate (12.6 g, 55.6 mmol), ethanol (15 mL), and concentrated ammonium hydroxide (14.8 N, 5.6 mL, 83 mmol) were stirred at room temperature for 16 h. The solvent was evaporated and the residue chromatographed on a wet-packed silica gel column (5.5×31 cm) eluting with 90:10 methylene chloride/methanol. The appropriate fractions were combined and evaporated to give 9.5 g (86%) of ethyl (3-amino-2-fluoro-3-oxopropyl)(methyl)phosphinate as a clear oil. Data: 1H NMR (300 MHz, CDCl3) δ6.62 (s, 1H), 6.33 (s, 1H), 5.10-5.42 (m, 1H), 4.02-4.18 (m, 2H), 2.19-2.70 (m, 2H), 1.60 (d, J=14 Hz, 3H), 1.34 (m, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.[CH2:21]([NH2:23])[CH3:22]>ClCCl>[CH2:21]([NH:23][C:15](=[O:16])[CH:14]=[CH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)[CH3:22]
Reactant: O=C(Cl)C=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)C=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 72 %

Procedure:
The title compound is prepared in analogy to example 9, using crude 3-[4-(3-fluoro-benzyloxy)-phenyl]-acryloyl chloride and a 2 M solution of ethylamine in dichloromethane. Colorless solid. Yield=72%. MS: m/e=300.3 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][SH:9])=[CH:4][CH:3]=1.Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][C:11]2[CH:21]=[C:15]3[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]3[C:13](=[O:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(SCc1ccc(Cl)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E62 starting from (4-chlorophenyl)methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(O)cc1
Product: COc1ccc(Oc2nc(Cl)ncc2F)cc1

Procedure:
Using an analogous method to that described in Method 28, but starting from 2,4-dichloro-5-fluoropyrimidine and 4-methoxyphenol, the product was obtained. NMR: 3.84 (s, 3H), 6.79-7.00 (m, 2H), 7.06-7.18 (m, 2H), 8.31-8.36 (m, 1H); MS (M+): 254, 256.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:5]=[O:6]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C=O)cc1Br
Temperature: 90 °C

Procedure:
To a solution containing 0.5 g 3-bromo-4-fluorobenzaldehyde and 20 ml of DMSO was added 0.49 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and poured into water. Sodiumhydrogencarbonate was added and the product extract with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 0.69 g. 1H-NMR (DMSO-d6, 400 MHz): 3.52 (s, 3 H, CH3), 8.10-8.47 (m, 3 H, Ar), 10.01 (d, 1 H, CHO).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C@:22]12[C@:21]3([CH3:26])[CH2:20][CH2:19][C@H:18]4[C:17]([CH3:27])([CH3:28])[C@@H:16]([OH:29])[CH2:15][CH2:14][C@:13]4([CH3:30])[C@H:12]3[CH2:11][CH2:10][C@@H:9]1[C@@H:8]1[C@@:7]3([CH2:31][O:32][C@H:4]1[C:2]([CH3:1])([CH3:3])[CH2:5][CH2:6]3)[CH2:24][CH2:23]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC[C@]23CC[C@]4(C)[C@H](CC[C@@H]5[C@@]6(C)CC[C@H](O)C(C)(C)[C@@H]6CC[C@]54C)[C@H]2[C@H]1OC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
In 100-ml flask stir 2 g of Betulin in 50 ml of CH2Cl2 at 0° C. Add 5 ml of 99% CF3COOH and stir for 30 minutes. Pour reaction mixture in 100 ml of cracked ice and separate the organic part. Extract with CH2Cl2 (3×10 ml) and wash combined organic extracts with conc. NaHCO3 (2×20 ml) and water (2×20 ml), and dry the extract over Na2SO4 (anh.). Evaporation of solvent gives 1.98 g of Allobetulin, which was recrystallized from hexane-dichloromethane to yield white needles mp. 268-269° C. [lit. 265-268], IR (KBr) 3448.5, 2941.5, 2866.6, 1780.7, 1456.6, 1384.4, 1168.9, 1035.0, cm−1; 1H NMR (CDCl3) d 3.75 (D, J=10.3 Hz, 1H, 28-H), 3.51 (S, 1-H, 19-H), 3.41 (D, J=10.3 Hz, 1H, 28-H), 3.18 (DD, 1H, 3-H), 0.74, 0.76, 0.81, 0.88, 0.89, 0.94, 0.94 (all S, 7×3H, 27-, 23-, 24-, 25-, 26-, 29-, 30-Me), 1.01-1.74 (complex CH—, CH2, 25H,); 13C NMR (CDCl3) d 88.41, 79.38, 71.49, 55.77, 51.35, 47.07, 41.78, 40.99, 40.88, 40.87, 39.16, 37.52, 36.95, 36.51, 34.40, 34.18, 32.96, 29.08, 28.27, 27.57, 26.72, 26.72, 26.50, 24.82, 21.26, 18.54, 16.79, 15.96, 15.72, 13.82; MS (EI) 442, 424, 411, 371, 355, 303, 273, 257, 245, 231, 220, 207, 203, 189, 177, 162, 149, 135, 121, 107.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCN(CC)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc(N)cc1Cl
Reaction time: 7.5 h

Procedure:
A suspension of 0.700 g (2.884 mmol) (2-chloro-4-nitro-benzyl)-diethyl-amine (Z35a) and 0.400 g Raney nickel in 20 mL THF was hydrogenated for 7.5 h at RT and 25 psi. The catalyst was filtered off and the filtrate was evaporated down i. vac. The crude product was purified by column chromatography (Alox, neutral, act. II-III, petroleum ether/EtOAc 4:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:18]=1.[CH:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>O>[CH3:26][C:21]1[CH:20]=[CH:19][C:24]([O:25][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](/[CH:10]=[CH:11]/[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:7][C:6]=3[CH:18]=2)=[CH:23][CH:22]=1
Reactant: Brc1ccc2oc(/C=C/c3ccccc3)nc2c1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(Oc2ccc3oc(/C=C/c4ccccc4)nc3c2)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
Under an argon stream, a mixture of 5-bromo-2-[(E)-2-phenylethenyl]benzoxazole (Compound of Reference Example 43) (105 mg), p-cresol (45 mg), potassium carbonate (97 mg), copper oxide(II) (70 mg) and pyridine (1.5 ml) was stirred at 130° C. for 24 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of potassium hydrogen sulfate and water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:6, v/v) was concentrated under reduced pressure, and the resulting crystals were collected by filtration to obtain 5-(4-methylphenoxy)-2-[(E)-2-phenylethenyl]benzoxazole (69 mg, 60%). The compound was recrystallized from ethyl acetate-hexane.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:26][CH3:27])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C(O)C.[BH4-].[Na+].[NH3:33]>C([O-])C.C([O-])C.C([O-])C.C([O-])C.[Ti+4]>[NH2:33][CH:1]([C:4]1[C:5]([O:26][CH3:27])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Reactant: N
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Titanium tetraethanolate (2.70 mL, 12.9 mmol) was added to a mixture of benzyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (2.5 g, 6.4 mmol) in 2.0 M ammonia in ethanol (16.1 mL, 32.2 mmol) at 0° C. The solution was stirred at 60° C. under N2 overnight. Sodium tetrahydroborate (0.366 g, 9.67 mmol) was added to the above mixture at 0° C. and the solution was stirred at room temperature for another 1 hour. The reaction mixture was quenched with 2 M ammonia in water and filtered. The solid was washed with acetonitrile. The solvent was removed and the residue was diluted with dichloromethane, washed with water and brine, dried over MgSO4 and concentrated to give the desired product (2.47 g, 98%). LCMS calculated for C21H26ClN2O3 (M+H)+: m/z=389.2. found: 389.1.