Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:26]2([CH3:31])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:20][C:21]([O:23]CC)=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[C:3]([NH:18][CH:19]([C:26]2([CH3:31])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F)C1(C)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(CC(=O)O)Nc2nc(-c3n[nH]c4ncc(F)cc34)ncc2F)CCCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of racemic ethyl 3-[[5-fluoro-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(1-methylcyclopentyl)propanoate, 149a, (0.110 g, 0.256 mmol) in THF (30 mL) was added a solution of lithium hydroxide hydrate (0.043 g, 1.022 mmol) in H2O (20 mL). The reaction mixture was stirred at 70° C. overnight. The organic solvent was removed under reduced pressure and the remaining aqueous phase was used directly in the purification via preparatory HPLC. The resulting HPLC fractions were extracted with EtOAc. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford the desired product: 1H NMR (400 MHz, MeOD) δ 8.64 (dd, J=8.4, 2.4 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J=4.4 Hz, 1H), 5.19 (d, J=8.7 Hz, 1H), 2.78 (qd, J=15.9, 6.6 Hz, 2H), 1.85-1.57 (m, 6H), 1.48 (dd, J=11.8, 6.0 Hz, 1H), 1.36 (dt, J=12.0, 6.0 Hz, 1H), 1.11 (s, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.37 min, (M+H) 403.22.
Reaction SMILES: [CH2:1]([N:5]1[CH:21]=[C:8]2[C:9]3[N:10]([N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH:11]=[N:12][C:7]2=[N:6]1)[CH2:2][CH2:3]C.[K+].[Br-]>>[CH2:1]([N:5]1[CH:21]=[C:8]2[C:9]3[N:10]([N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH:11]=[N:12][C:7]2=[N:6]1)[CH2:2][CH3:3]
Reactant: CCCCn1cc2c(ncn3nc(-c4ccco4)nc23)n1
Agent: [Br-]
Agent: [K+]
Product: CCCn1cc2c(ncn3nc(-c4ccco4)nc23)n1

Procedure:
8-Butyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (Compound 21) yield 50%, pale yellow solid m.p. 245-247° C. (EtOAc-light petroleum); IR (KBr): 1610, 1500 cm−1; 1H NMR (DMSO-d6) δ 0.9 (m, 3H); 1.3 (m, 2H); 1.9 (m, 2H); 4.5 (t. 2H, J=7.2); 6.2 (m, 1H); 7.3 (m, 1H); 8.0 (m, 1H); 8.9 (s, 1H); 9.4 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[CH3:2].[CH2:24]=[O:25]>CS(C)=O.C(Cl)Cl>[OH:25][CH2:24][CH:1]([C:3]1[CH:4]=[C:5]([C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[CH3:2]
Reactant: C=O
Reactant: CCc1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(CO)c1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 110.2 %

Procedure:
A suspension of 2-(3-ethyl-4-nitrophenyl)-2-phenyl-1,3-dioxane (17) (20.0 g, 63.8 mmol), paraformaldehyde (6.5 g, 72.6 mmol) and a methanolic solution of Triton B (35%, 17 mL) in DMSO (100 mL) was stirred for 2 hours at 85° C. The reaction mixture was then cooled to ambient temperature, diluted with CH2Cl2 (200 mL), washed with water (2×200 mL), partially concentrated in vacuo (for azeotropic drying) and filtered over silica gel (35 g). The filtrate was then evaporated in vacuo to give 24.15 g (approx. 70.3 mmol, 110%) of the crude product as a yellow oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][CH2:32][C:33]([CH:35]=[N+]=[N-])=[O:34])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOCC.[ClH:43].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][CH2:32][C:33]([CH2:35][Cl:43])=[O:34])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)NCCC(=O)C=[N+]=[N-]
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)NCCC(=O)CCl

Procedure:
Boc-tryptophyl-leucyl-β-alanyl-diazomethane (Section 5.7.1) (0.24 g, 0.47 mmol) was dissolved in ethyl acetate (50 ml). Ether/HCl (40 ml) was added followed by 5% NaHCO3 (60 ml) 1 minute later. The mixture was agitated to neutralise the acid and the aqueous layer was removed. The organic phase was dried over magnesium sulphate and reduced to dryness. The peptide was recrystallised from ethyl acetate/petrol ether (40°/60° C.) and then diethyl ether/petrol ether (40°/60° C.). Yield 0.2 g (82%), m.p. 79°-81° C. The product was homogeneous as judged by tlc in chloroform/methanol (4:1) (Rf 0.770) or chloroform/methanol (1:1) (Rf 0.777). (Found: C, 59.83; H, 7.35; N, 10.81. C26H37O5N4Cl1 requires C, 60.00; H, 7.11; N, 10.77%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Cl:13])=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].BrC[C:18]([CH2:26][CH3:27])([CH2:22][CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20].Cl>O>[NH2:6][C:5]1[CH:7]=[C:8]([Cl:13])[C:9]([O:11][CH3:12])=[CH:10][C:4]=1[S:3][CH2:2][C:18]([CH2:26][CH3:27])([CH2:22][CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20]
Reactant: COc1cc2sc(N)nc2cc1Cl
Reactant: CCCCC(CC)(CBr)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)(CSc1cc(OC)c(Cl)cc1N)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4 (20.0 g) in H2O (200 ml) was added KOH (100 g). The slurry was refluxed for 7 h and allowed to cool to RT. To the dark solution was added 2 (33.2 g) in one portion. The reaction mixture was stirred for 18 h at which point the pH was adjusted to 4 with HCl. The mixture was transferred to a separatory funnel and extracted three times with ethyl acetate. The organic layer was dried and concentrated. The product was purified by column chromatography on silica gel eluting the product with 10% ethyl acetate/petroleum ether giving 5 (30.1 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:21]([CH2:33][CH3:34])=[C:22]([C:24](N2CCC(=O)CC2)=[O:25])[N:23]=1>C1COCC1.CCCCCC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[C:21]([CH2:33][CH3:34])=[C:22]([C:24]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[O:25])[N:23]=1
Reactant: Brc1cccs1
Reactant: CCc1c(C(=O)N2CCC(=O)CC2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1c(C(=O)c2cccs2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 2-bromothiophene (0.22 g, 1.36 mmol) in 2 mL THF was added 0.84 mL of a 1.6 M solution of BuLi in hexane under argon at −78° C. with stirring. The stirring was continued for 1 h. To this was added a solution of 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazol-4-yl]carbonyl}-4-piperidinone in 2 mL THF. The resultant mixture was stirred and gradually allowed to warm up to rt overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude product was purified by HPLC to yield [2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazol-4-yl](2-thienyl)-methanone as a solid (60 mg, 31%): Rf=0.13 (1:5 ethyl acetate/hexanes).
Reaction SMILES: O1CCOCC1.Cl[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na].[CH3:22][S:23]([N:26]1[CH2:30][C@H:29](OS(C)(=O)=O)[CH2:28][C@H:27]1[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([N:26]1[CH2:30][C@@H:29]([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:28][C@H:27]1[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])(=[O:24])=[O:25]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1S(C)(=O)=O
Agent: [Na]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](P(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To 150 ml of dioxane were added 11.39 g (0.052 mol) of chlorodiphenylphosphine and 2.6 g (0.114 mol) of sodium, and the mixture was refluxed for 4 hours in nitrogen atmosphere. After allowing the mixture to stand for cooling, 50 ml of tetrahydrofuran was added to the reaction mixture, and a solution of 10.45 g (0.027 mol) of (2S,4R)-N-methanesulfonyl-2-tert-butyldimethylsilyloxymethyl-4-methanesulfonyloxypyrrolidine [V] in 100 ml of tetrahydrofuran was added dropwise to the mixture lest any air should enter in the reaction system. The mixture was stirred in nitrogen atmosphere at 0° C. for 2 hours and then at room temperature overnight and then any insoluble matter was removed, for example, by filtration. The filtrate was concentrated until dryness under reduced pressure and the residue was purified by column chromatography on silica gel whereby 7.93 g (yield: 62%) of an oily substance was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH:5]=[C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=O)[O:7]1.O.[NH2:21][NH2:22]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=[O:7])[NH:22][N:21]=1
Reactant: NN
Reactant: Nc1cc(C=C2OC(=O)C3=C2CCCC3)ccc1F
Solvent: O
Solvent: CCO
Product: Nc1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F
Temperature: 0 °C

Procedure:
To a solution of EXAMPLE 2B (1.42 g) in ethanol (10 mL) was added hydrazine monohydrate (0.27 mL). The mixture stirred at reflux for 1 hour, cooled to 0° C., and filtered. The solid was washed with water and dried. 1H NMR (CD3OD) δ 1.63-1.75 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53 (m, 2H), 3.84 (s, 2H), 6.42-6.49 (m, 1H), 6.64 (dd, J=8.6, 2.2 Hz, 1H), 6.86 (dd, J=11.2, 8.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:12]=[C:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:10]([CH3:20])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1n[nH]c(Cc2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCCOC(=O)c1nc(Cc2ccccc2)n(C)n1
Temperature: 23 °C
Reaction time: 72 h

Procedure:
5-Benzyl-1H-[1,2,4]triazole-3-carboxylic acid butyl ester (100 mg, 0.386 mmol) was dissolved in acetone (3 ml), to which were added potassium carbonate (80 mg, 0.578 mmol) and iodomethane (27 μl, 0.432 mmol) as a solution in acetone (2 ml) at 23° C. The reaction mixture was stirred at 23° C. for 72 h, then filtered and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate; 25 g column; flow 40 ml/min; 0% ethyl acetate to 100% ethyl acetate in 20 min) to give the title compound. UPLC-MS (method F) Rt=0.96 min, [M+H]+=274.3.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH:16][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)C1CCCCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 86b) and cyclohexanecarboxylic acid as brown solid (31%). MS 414 (MH+).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:12]([CH3:14])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][N:5]=[C:6]([C:12]([CH2:14][Br:1])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC)C(=O)CBr

Procedure:
Bromine (100 g.) was dropwise added over 40 minutes under reflux to a solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (100 g.) in a mixture of carbon tetrachloride (300 ml.) and acetic acid (300 ml.). The mixture was stirred at 70° C. to 80° C. until the evolution of hydrogen bromide ceased. The reaction mixture was washed twice with water (300 ml.), a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solution was treated with activated charcoal (2 g.) and concentrated under reduced pressure to give ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (120.8 g.).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8].C([O:16][C:17]([C:19]([CH3:67])([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([CH3:48])([C:43]([O:45]CC)=O)[CH3:42])=[CH:36][C:35]=3[OH:49])[N:31]=[C:30]([C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57]([CH3:64])([C:59]([O:61]CC)=O)[CH3:58])=[CH:52][C:51]=3[OH:65])[N:29]=2)=[C:24]([OH:66])[CH:23]=1)[CH3:20])=O)C.C1(C)C(C)=[CH:70][CH:71]=[CH:72][CH:73]=1>CCCCCC.ClCCl>[CH2:5]([N:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:43]([C:41]([CH3:48])([O:40][C:37]1[CH:38]=[CH:39][C:34]([C:32]2[N:31]=[C:30]([C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57]([CH3:64])([C:59]([N:29]([CH2:28][CH2:25][CH2:24][CH3:23])[CH2:30][CH2:50][CH2:51][CH3:52])=[O:61])[CH3:58])=[CH:52][C:51]=3[OH:65])[N:29]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][C:19]([CH3:67])([C:17]([N:31]([CH2:73][CH2:72][CH2:71][CH3:70])[CH2:32][CH2:34][CH2:35][CH3:36])=[O:16])[CH3:20])=[CH:23][C:24]=3[OH:66])[N:33]=2)=[C:35]([OH:49])[CH:36]=1)[CH3:42])=[O:45])[CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(-c2nc(-c3ccc(OC(C)(C)C(=O)OCC)cc3O)nc(-c3ccc(OC(C)(C)C(=O)OCC)cc3O)n2)c(O)c1
Reactant: Cc1ccccc1C
Reactant: CCCCNCCCC
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCN(CCCC)C(=O)C(C)(C)Oc1ccc(-c2nc(-c3ccc(OC(C)(C)C(=O)N(CCCC)CCCC)cc3O)nc(-c3ccc(OC(C)(C)C(=O)N(CCCC)CCCC)cc3O)n2)c(O)c1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
21 ml of a 2.0 M solution of trimethylaluminium in hexane are added under argon to 5.5 g (0.042 mol) of dibutylamine in 35 ml of anhydrous dichloromethane. After 15 minutes, 10.5 g (0.014 mol) of 2,4,6-tris(4-[1-ethoxycarbonyl-1-methylethoxy]-2-hydroxyphenyl)-1,3,5-triazine (Compound 1) are added to the reaction mixture. After 1 day 10 ml of anhydrous xylene are added and the dichloromethane is distilled off. The reaction mixture is subsequently heated at 130° C. for 2 days and then 10 ml of 20% HCl are added. The reaction mixture is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate. The title product is obtained after column chromatography (Compound 15: 1H NMR(CDCl3): 0.80 (t, J=7.1 Hz,9H), 0.90 (t, J=7.1 Hz,9H), 1.12-1.4 (m, 24H), 1.71 (s, 27H), 3.29-3.35 (m, 6H), 3.50-3.55 (m, 6H), 6.39-6.60 (m, 6H), 8.00-8.02 (m, 3H), 13.24 (s, 3H)) and also
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3(O)[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.BrC1C=CC(C#CC2C=CC(OC)=CC=2)=CC=1.C(C1CCC(=O)CC1)CCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: CCCCCC1CCC(O)(c2ccc(C#Cc3ccc(OC)cc3)cc2)CC1
Agent: CCCCCC1CCC(=O)CC1
Agent: COc1ccc(C#Cc2ccc(Br)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CC=C(c2ccc(C#Cc3ccc(OC)cc3)cc2)CC1

Procedure:
0.2 mol of 4-methoxy-4'-(1-hydroxy-4-pentylcyclohexyl)-tolan (prepared by reaction of a Grignard compound of 4-bromo-4'-methoxytolan with 4-pentylcyclohexanone) is heated in 400 ml of toluene and with 1 g of p-toluenesulfonic acid for 1 hour using a water separator. The reaction mixture is washed, dried and evaporated. Customary working up gives 1-(4-methoxyphenyl)-2-[4-(4-pentylcyclohexen-1-yl)-phenyl]-acetylene.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=1.C(O)(=O)C>O>[N:1]1([CH2:7][C:8]2[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(CN2CCCC2)[nH]c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.8 %

Procedure:
To a solution of 1.78 g of pyrrolidine in water (20 ml), 1.33 g of 6-chloromethyluracil were added. The resulting mixture was stirred at room temperature for 24 hours and neutralized with acetic acid. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was washed with methanol and then filtered, whereby 466 mg of the title compound were obtained (yield: 29%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[C:28]=2[CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[C:33]5[C:28]=4[CH:27]=[N:26][NH:25]5)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccc4[nH]ncc34)c2n1C
Temperature: 140 °C
Yield: 39.6 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 1H-indazole-4-boronic acid (0.054 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 30 min at 140° C. by microwave irradiation. 1H-indazole-4-boronic acid (0.054 g, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) were added and the resultant mixture heated for 30 min at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 426 as a white solid (0.044 g, 40%). LCMS (Method K): RT 2.82, 2.99 min [M+H]+ 428.1. 1H NMR (DMSO-d6, 400 MHz): δ 13.30 (1H, s), 8.23-7.98 (1H, m), 7.77-7.60 (4H, m), 7.51-7.48 (1H, m), 7.36-7.24 (2H, m), 7.23-7.08 (2H, m), 5.59-5.54 (1H, m), 3.00 (3H, d, J=8.05 Hz), 1.57 (3H, dd, J=6.69, 1.65 Hz). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [CH3:1][Li].[OH:3][C:4]1C=C2[C:7]([C:8]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[CH:9]C(=O)O2)=[CH:6][CH:5]=1.[CH3:25][CH2:26][O:27][CH2:28][CH3:29]>>[CH3:25][C:26]1([CH3:1])[CH:9]=[C:8]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[C:7]2[C:28](=[CH:29][C:4]([OH:3])=[CH:5][CH:6]=2)[O:27]1
Reactant: O=c1cc(-c2ccc3ccccc3c2)c2ccc(O)cc2o1
Reactant: CCOCC
Reactant: [Li]C
Product: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Reaction time: 5 h

Procedure:
To a stirred solution of methyl lithium (0.04 mole, 20 ml of a 1.9M solution in ether) under nitrogen at ambient temperature was added portionwise 7-hydroxy-4-(2-naphthyl)coumarin (2.89 g, 0.01 mole). After 5 hours the solution was decomposed with acid to give 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol as a crude dark brown foam (2 g) which was used without further purification.
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2].[CH:10]1([O:16][C:17]2[S:18][C:19]([C:23]#[N:24])=[C:20]([OH:22])[N:21]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:25](N(CC)CC)C>>[CH:10]([O:6][CH:7]([CH3:8])[CH3:25])([CH3:15])[CH3:11].[CH:10]1([O:16][C:17]2[S:18][C:19]([C:23]#[N:24])=[C:20]([O:22][P:1]([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2])[N:21]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: N#Cc1sc(OC2CCCCC2)nc1O
Reactant: CCN(CC)CC
Reactant: CCOP(=S)(Cl)OCC
Product: CC(C)OC(C)C
Product: CCOP(=S)(OCC)Oc1nc(OC2CCCCC2)sc1C#N
Reaction time: 72 h
Yield: 80.6 %

Procedure:
A mixture of 12.44 g of diethyl chlorothiophosphate, 6.67 g of triethylamine and 15 g of 2-cyclohexyloxy-4-hydroxy-5-cyano-thiazole was stirred for 3 days and then concentrated to dryness. The residue was added to water and the aqueous phase was extracted with ether. The ether phase was dried and evaporated to dryness. The residue was crystallized from pentane and then isopropyl ether to obtain 10 g of 2-cyclohexyloxy-4-diethoxythiophosphoryloxy-5-cyano-thiazole in the form of white crystals melting at 58° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([S:8][CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[N:6][N:5]=[N:4]1.C(=O)(O)[O-].[Na+].O1CCCC1.Cl[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34]>O>[CH3:2][N:3]1[C:7]([S:8][CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][N:11]2[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])=[N:6][N:5]=[N:4]1
Reactant: Cn1nnnc1SCC1NCCc2cc(O)c(O)cc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnnc1SCC1c2cc(O)c(O)cc2CCN1C(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
A suspension of 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 g) in water (300 ml) was dissolved at 61° to 65° C. To the solution was added sodium bicarbonate (13.3 g) over 15 minutes at the same temperature. Tetrahydrofuran (250 ml) was added to the suspension at 50° C. The suspension was cooled and weakly alkalified by adding sodium bicarbonate (30 g) at 0° to 3° C. To the mixture was added 2,2,2-trichloroethyl chloroformate (40.2 g) over 30 minutes below 3° C. The resulting mixture was stirred for 30 minutes at 0° C. Water (300 ml) was added to the reaction mixture and the mixture was twice extracted with ethyl acetate (900 ml and 600 ml). The extract was washed with a sodium chloride aqueous solution (300 ml) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized with ether to give 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-(2,2,2-trichloroethoxycarbonyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (40.4 g), mp 201° to 207° C.