Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.C(O)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19](=[O:22])[CH2:20][Cl:21])=[O:16])([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+]>C(O)(=O)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:19]([OH:22])[CH2:20][Cl:21])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 72.6 %

Procedure:
Ethyl acetate (4.2 ml) and ethanol (16.7 ml) were added to (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g). Sodium borohydride (133 mg) was added in portions to the obtained mixture at −10° C., and they were stirred for 1 hour 40 minutes. Acetic acid (0.40 ml) was added to the reaction mixture to terminate the reaction. The reaction mixture was slowly heated to 60° C. for the duration of 1 hour and then stirred at 60° C. for 30 minutes. The reaction mixture was slowly cooled to −10° C. for the duration of 1 hour 50 minutes and then stirred at −10° C. for 6 hours. The crystals thus formed were taken by the filtration, washed with 0° C. water and dried under reduced pressure to obtain intended (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[CH:41][C:40]([C:43]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[N:42]=[CH:41][C:40]([C:43]4([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]4)=[CH:39][CH:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: NC(=O)C1(c2ccc(Cl)nc2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 47 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-chloro-pyridin-3-yl)-cyclopropanecarboxylic acid amide following a procedure analogous to that described in Example 1. Yield: 47% of theory; LC (method 1): tR=1.85 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:19]=[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][N:13]4[N:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC#N>[N:19]1[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[N:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=12
Reactant: C1CCn2nc(C3CCC4(CC3)OCCO4)nc2C1
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(c2nc3n(n2)CCCC3)CC1

Procedure:
A solution of 2-(1,4-dioxa-spiro[4.5]dec-8-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (1.05 g, 4 mmol, prepared according to the literature procedure: Quanrui Wang, Atef Amer, Susanne Mohr, Eveline Ertel, Johannes C. Jochims, Tetrahedron, 1993, 49(44), 9973-9986) in CH3CN (20 mL) and 2N HCl (30 mL) was stirred at rt for 2 h. Evaporation to dryness gave the intermediate as a HCl salt.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+:20].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][C:14](=[O:16])[NH:20][C:10](=[O:11])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: [NH4+]
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)CC(=O)N1
Temperature: 160 °C
Yield: 86.6 %

Procedure:
A suspension of 2,2′-(benzylazanediyl)diacetic acid (5.0 g, 22.4 mmol) and ammonium formate (4.2 g, 67.2 mmol) in N,N-dimethylformamide (75 mL) was stirred to reflux (160° C.) for 2 days. After cooling to room temperature, the reaction mixture was diluted by successive addition of ethyl acetate (150 mL) and a saturated solution of sodium hydrogen carbonate (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL) and the combined organic phases were washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give the title product as a yellow liquid (3.96 g, 87%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.CN(C)CC.[Si](Cl)(C)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][CH:49]([C:52]([F:55])([F:54])[F:53])[CH2:48][CH2:47]3)=[O:45])=[CH:40][CH:39]=2)=[CH:33][C:32]=1[Cl:56]>C1COCC1.CCOC(C)=O.CCCCCCC>[Cl:56][C:32]1[CH:33]=[C:34]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([N:46]3[CH2:51][CH2:50][CH:49]([C:52]([F:55])([F:54])[F:53])[CH2:48][CH2:47]3)=[O:45])=[CH:42][CH:43]=2)[CH:35]=[C:36]([Cl:37])[C:31]=1[CH2:30][C@@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:7][C:6]1=[O:8]
Reactant: O=C(c1ccc(-c2cc(Cl)c(CBr)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reactant: O=C1CC[C@@H](CO)O1
Agent: CCN(C)C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1O[C@H](CO)C[C@H]1Cc1c(Cl)cc(-c2ccc(C(=O)N3CCC(C(F)(F)F)CC3)cc2)cc1Cl
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
Dissolve (S)-5-Hydroxymethyl-dihydro-furan-2-one (1.21 g, 1 eq.) in THF (16 mL) and cool to −10° C. To this add dimethylethylamine (1.8 mL, 1.5 eq.) followed by the dropwise addition of TMS-Cl (1.46 mL, 1.1 eq.) Allow the reaction to stir for 1.5 hours at −10° C. Gas Chromatography confirms complete consumption of the (S)-5-Hydroxymethyl-dihydro-furan-2-one. Filter the mixture and wash with additional THF (25 mL). Cool the solution to −78° C. To this add LiHMDS (10 mL, 1.23 eq. to (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone) dropwise and allow to stir at −78° C. for 30 minutes. Add (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone (4 g, 0.76 eq. to (S)-5-Hydroxymethyl-dihydro-furan-2-one) and keep the reaction at −78° C. After 1 hour, TLC (50% EtOAc/Heptane) shows approximately 50% (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone. At the end of the day, add LiHMDS (3 mL) and allow to warm to room temperature overnight. TLC (50% EtOAc/Heptane) still shows a small amount of (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone. Quench the reaction with phosphoric acid:water (1:3) (50 mL) and allow to stir at room temperature for 1 hour. Extract the aqueous layer with EtOAc (3×100 mL). Combine the organic layers, dry and concentrate. Pass the crude oil through a silica gel plug (EtOAc) to give the titled compound (2.57 g, 60% yield).
Reaction SMILES: C(O)(=O)[C:2]1([CH2:12][CH2:11][CH:7]([C:8](O)=O)[C:4]1([CH3:6])C)C.[CH2:15]([N:18]1[CH2:23][C@@H:22]([CH3:24])[NH:21][CH2:20][C@@H:19]1[CH3:25])[CH:16]=[CH2:17].C(=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH2:15]([N:18]1[CH2:23][C@@H:22]([CH3:24])[N:21]([CH2:8][C:7]2[CH:4]=[CH:6][CH:2]=[CH:12][CH:11]=2)[CH2:20][C@@H:19]1[CH3:25])[CH:16]=[CH2:17]
Reactant: C=CCN1C[C@@H](C)NC[C@@H]1C
Reactant: CC1(C(=O)O)CCC(C(=O)O)C1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1
Product: C=CCN1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the camphoric acid salt of (+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine from Preparation 1 (78.2 g) and benzaldehyde (26.5 g) in tetrahydrofuran (500 ml) containing glacial acetic acid (2 ml) was added sodium triacetoxyborohydride (93.3 g) portionwise over 10 minutes. The resulting mixture was stirred at room temperature for 4 hours. The reaction was partitioned between ethyl acetate (1500 ml) and aqueous sodium hydroxide (750 ml of 2N solution). The layers were separated and the organic phase was washed with 10% sodium metabisulphite solution (200 ml) and saturated brine solution. The organic layer was dried (MgSO4) and evaporated to dryness in vacuo to give the title compound, 52.1 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([S:29]C#N)=[C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:14]([SH:29])=[C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCNc1nc(CSCCNC(=O)OC(C)(C)C)c(SC#N)s1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCNc1nc(CSCCNC(=O)OC(C)(C)C)c(S)s1

Procedure:
2-(2-t-butoxycarbonylaminoethylamino)-4-(2-t-butoxycarbonylaminoethylthiomethyl)-5-thiocyanato-1,3-thiazole was reduced with sodium borohydride in a manner similar to that described in Example 44 to produce title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:24]#[N:25].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CC#N>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:24]#[N:25]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: COc1cc(C#N)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COc1cc(C#N)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCCN32)CC1
Temperature: 100 °C
Yield: 44.9 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (150 mg, 0.643 mmol), 3-methoxy-4-(piperazin-1-yl)benzonitrile hydrochloride (163 mg, 0.643 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg, 1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) were suspended in Propiononitrile (Volume: 1931 μl) and heated in a closed vial at 100° C. for 2 h. The reaction mixture became a dark brown solution. It was diluted with MeCN (4 mL) and concentrated in vacuo to about 3 mL. The resulting precipitate was filtered, recrystallized from MeCN (5 mL) and dried in vacuum to afford (S)-3-methoxy-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (125 mg, 0.289 mmol, 44.9% yield) as an off-white solid. 1H NMR (DMSO-d6) δ 10.48 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H), 6.93-6.98 (m, 2H), 4.50 (d, J=12.9 Hz, 1H), 3.79-3.87 (m, 4H), 3.34-3.40 (m, 2H), 3.07 (br. s., 4H), 2.60 (td, J=12.7, 2.7 Hz, 1H), 2.47 (br. s., 4H), 2.02 (br. s., 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.4 Hz, 1H), 1.32-1.57 (m, 3H); [M+H] calc'd for C24H28N6O2, 433; found, 433.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14](B2OCC(C)(C)CO2)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([Cl:33])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([Cl:33])[CH:26]=2)[C:8]2[O:9][C:10]([F:12])([F:13])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(c(B3OCC(C)(C)CO3)c1)OC(F)(F)O2
Reactant: COc1ccc(Br)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(c(-c3ccc(OC)c(Cl)c3)c1)OC(F)(F)O2
Yield: 16 %

Procedure:
1.9 g of 7-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (example YY, step 4), 1.5 g of 4-bromo-2-chloro-1-methoxybenzene, 152 mg of triphenylphosphine, 65 mg of palladium(II) acetate, and 2.4 g of K2CO3 were stirred in 30 ml of DMF and 3 ml of water under an argon atmosphere at 100° C. for 4 h. 200 ml of water were then added and the mixture was extracted three times using 100 ml of EA each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:5 yielded 330 mg of the title compound, colorless oil. Rf (EA/HEP 1:5)=0.29
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9](=[O:16])[N:10]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]1)(C)(C)C.[ClH:25].O1CCOCC1>>[ClH:25].[NH2:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([N:10]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC(=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-[1-Benzyl-2-oxo-2-(3-oxo-pyrrolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (552 mg, 1.7 mmol) was dissolved in 4M HCl-dioxane (6.2 mL) at 0° C. The mixture was stirred at 25° C. for 1 hour, concentrated and the residue triturated with ether to give alight brown solid. Yield, 482 mg, 108%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[CH:9]=2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[OH-].[Na+].[CH:31](OC)(OC)OC>FC(F)(F)C(O)=O.O1CCCC1>[CH3:31][NH:14][C:11]1[CH:12]=[N:13][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1N
Reactant: COC(OC)OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 35 g (124 mmol) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-ylamine in 270 ml trimethyl orthoformate and 8 drops trifluoroacetic acid was heated for 3 h at 130° C. The reaction mixture was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 100 ml tetrahydrofuran and was added dropwise under ice cooling to 9.4 g (248 mmol) lithium aluminum hydride in 300 ml tetrahydrofuran. The reaction mixture was stirred for lh at room temperature, cooled to 0° C. again and acidified (pH 1-2) by addition of 28% hydrochloric acid solution. After stirring for 5 min, 28% sodium hydroxide solution was added to reach pH 10. The solution was filtered over celite, evaporated and purified by flash chromatography to give 23.6 g (64%) of the title compound as a light brown oil.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1[C:25]2[C:20](=CC=CC=2)[CH:19]=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27]>>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:27][C:26]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:25][CH:16]=2)=[O:28])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Product: O=C(C=Cc1ccc(Oc2ccccc2)cc1)c1ccccc1

Procedure:
Synthesised according to example 1.59.1 using 4-phenoxybenzaldehyde (3.0 g, 15.1 mmol) and 1-(naphthalen-2-yl)ethanone (2.58 g, 15.1 mmol); pale yellow solid; yield: 4.70 g (89%);
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCCCC(=O)O)cc3)cc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)pentanoate (1.0 equiv.) (from Example 139) in ethanol (0.10 M) was added anhydrous sodium hydroxide (2.0 equiv.) and the resulting mixture was allowed to stir at 80° C. for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and water. The biphasic layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-10% methanol in dichloromethane to furnish 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)pentanoic acid as a solid. 1H NMR (Methanol-d4): δ 8.61 (s, 1H), 8.57 (s, 1H), 8.20 (d, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 7.07 (d, 2H), 6.81 (d, 2H), 3.93 (t, 2H), 3.18 (t, 2H), 3.00 (t, 2H), 2.48 (s, 3H), 2.25 (t, 2H), 1.74-1.81 (m, 2H), 0.86-0.96 (m, 2H). LRMS [M+H]=430.2
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([C:25]#[CH:26])[CH:24]=2)[O:21][C:20]([CH3:28])([CH3:27])[CH2:19][C:18]3([CH3:30])[CH3:29])=[O:13])=[CH:7][C:6]=1[F:31])C.[OH-].[Li+]>CO.O1CCCC1.O>[C:25]([C:23]1[CH:24]=[C:15]([NH:14][C:12](=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:32])=[O:3])=[C:6]([F:31])[CH:7]=2)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([CH3:27])([CH3:28])[CH2:19][C:18]2([CH3:30])[CH3:29])#[CH:26]
Reactant: C#Cc1cc(NC(=O)Nc2ccc(C(=O)OCC)c(F)c2)cc2c1OC(C)(C)CC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(NC(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of 4-[3-(8-ethynyl-2,2,4,4-tetramethyl-chroman-6-yl)-ureido]-2-fluoro-benzoic acid ethyl ester (Intermediate 212, 0.12 g) in methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treated with lithium hydroxide (0.177 g, 4.2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo, the residue was diluted with water and neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to afford the title compound as a solid (0.07 g, 46% for two steps).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]1.[CH2:13]([O:15][C:16](=[O:27])[C:17](=[CH:23]OCC)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:27])[C:17](=[CH:23][NH:12][C:11]1[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9][CH:10]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccnn1Cc1ccco1
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)OCC

Procedure:
163 g of 1-(2-furyl)methyl-5-aminopyrazole (1 mol) and 216 g of ethoxymethylene malonic acid diethyl ester (1 mol) are heated to 130° (bath temperature) until the theoretical amount of alcohol is distilled off. The remaining oil, [[[1-(2-furyl)methyl-5-pyrazolyl]amino]methylene]malonic acid diethyl ester, is recrystallized from methanol, yield 280 g (84%), m.p. 84°-86 °.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[C:13]1([CH2:12][CH2:11][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1ccccc1
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1C
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Equal molar amounts of triethoxysilane (5 mL) and styrene (3.1 mL) were combined with 10 microliters of a 5% platinum siloxane complex in xylene as shown by Karstedt, U.S. Pat. No. 3,775,452. After 30 minutes at 50° C. with stirring, there was obtained 45% yield of phenylethyltriethoxysilane based on gas chromatography analysis. The same reaction was repeated except that 0.25 g of β-cyclodextrin was added to the mixture. After 30 minutes at 50° C., there was obtained a 100% conversion to phenylethyltriethoxysilane based on gas chromatography analysis.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1>C1(OC)C=CC=CC=1>[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[S:29]([NH2:32])(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reaction time: 30 h

Procedure:
Trifluoroacetic acid was added (2 mL) to 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (113 mg, 0.2618 mmol, see step (e) above) and one drop (ca. 0.05 mL) of anisole (ca. 0.05 mL) was added to the mixture. The reaction mixture was stirred under N2 atmosphere for 30 h and then evaporated and co-evaporated with acetonitrile until TLC showed that it was pure. The crude product was used directly in the next step without further purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[CH:4][CH:3]=1>C(O)C>[N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1C=Cc1ccncc1
Agent: Cl
Solvent: CCO
Product: Nc1ccccc1C=Cc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.4 %

Procedure:
In a mixture of concentrated hydrochloric acid (14 ml) and ethanol (14 ml) was dissolved 2.87 g of 2-[2-(4-pyridyl)ethenyl]-1-nitrobenzene. To this solution was added a solution of stannous chloride dihydrate (8.59 g) in ethanol (25 ml) gradually dropwise under ice-cooling and the mixture was stirred at room temperature for 5 hours. After the solvent was evaporated off under reduced pressure, the residue was made basic with 30% aqueous sodium hydroxide solution and extracted with chloroform. The extract was dehydrated over anhydrous magnesium sulfate and the solvent was evaporated off to provide 2.2 g of the title compound as yellow solid. This product was used as a starting material without purification.