Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.C(Cl)Cl.C(OCC)(=O)C>C1COCC1>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@@H:12]([OH:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=C[C@H](O)CC[C@]3(C)[C@H]1CC2
Yield: 48 %

Procedure:
These syntheses are depicted in FIG. 1. Androsta-4,16-dien-3-one (4) was reduced at -55° with lithium tris (1, 2-dimethylpropyl) hydridoborate in THF (c) as described for the preparation of 2 (FIG. 1). Chromatography on silica gel with CH2Cl2 /ethyl acetate 9:1 gave pure axial alcohol 5 (48% yield) and pure equatorial alcohol 6 (48% yield). Analytical samples were further purified by recrystallization (from PE at -30° for 5, from cyclohexane at RT. for 6).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@H:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[C:45](=[O:47])[CH3:46].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:45]([C:31]1[CH:32]=[CH:33][C:34]([C:2]2[N:7]=[C:6]([C@H:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:16]([CH3:27])[CH:15]=3)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=2)=[CH:35][C:30]=1[O:29][CH3:28])(=[O:47])[CH3:46]
Reactant: CCCC[C@@H](Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(C)=O
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCC[C@@H](Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(C)=O)c(OC)c2)n1
Temperature: 80 °C
Yield: 74.2 %

Procedure:
Ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.11 mmol) was dissolved in DME (0.76 mL) and then treated with 1-[2-(methyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (41 mg, 0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and then a solution of Na2CO3 (49 mg, 0.46 mmol) in water (0.42 mL). The resulting mixture was then placed under nitrogen and heated at 80° C. for 18 h. The solvents were the removed under vacuum (Genevac) and the residue purified by mass directed autoprep HPLC) to give the title compound as an oil (39 mg).
Reaction SMILES: COC1C=CC=CC=1S[CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36][C:37]([F:47])([F:46])[O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[SH:45].C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:26][C:22]([S:21][C:18]1[S:17][C:16]([NH:15][C:14]([N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[CH2:12][CH2:11][CH2:10][S:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[O:38][C:37]([F:36])([F:46])[F:47])=[O:28])=[N:20][CH:19]=1)([CH3:27])[C:23]([OH:25])=[O:24]
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: FC(F)(F)Oc1ccccc1S
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2OC(F)(F)F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-trifluoromethoxy -thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][SiH:2]([CH3:10])[N:3]([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[CH2:4]([N:3]1[CH2:7][CH:8]([CH3:9])[Si:2]1([CH3:10])[CH3:1])[CH:5]=[CH2:6].[CH2:4]([N:3]1[CH2:7][CH2:8][CH2:9][Si:2]1([CH3:10])[CH3:1])[CH:5]=[CH2:6]
Reactant: C=CCN(CC=C)[SiH](C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: c1ccccc1
Product: C=CCN1CC(C)[Si]1(C)C
Product: C=CCN1CCC[Si]1(C)C
Temperature: 80 °C

Procedure:
Comparison Example 2. Into a glass tube with an outside diameter of 10 mm and a length of 10 cm were introduced 0.002 mL of a 20 weight % isopropanolic chloroplatinic acid solution and 2 mL of a mixture of 1 part N-dimethylsilyldiallylamine and 3 parts benzene, and the tube was sealed. The tube was heated for 17 hours at 80° C. The conversion of starting material was 100 weight %. 1-Allyl-2,2,3-trimethyl-1-aza-2-silacyclobutane and 1-allyl-2,2-dimethyl-1-aza -2-silacyclopentane were produced in a molar ratio of 66:34 and a combined yield of 55%.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8].C1(C)[CH:16]=[CH:15][C:14]([S:17](O)(=O)=O)=CC=1.[CH2:22]([N:24](CC)CC)[CH3:23].C1(C)C=CC(S(O)(=O)=[O:36])=CC=1.CN(C)C1C=CC=CC=1.NC(N)=S>>[CH3:16][C:15]1[CH2:14][S:17][C@@H:23]2[C@H:22]([NH2:24])[C:4](=[O:8])[N:3]2[C:7]=1[C:6]([OH:36])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)N1CCOC1=O
Agent: NC(N)=S
Solvent: CN(C)c1ccccc1
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.25 h
Yield: 347.7 %

Procedure:
To the above solution, there were added 0.28 mole of 3-trimethylsilyl-2-oxazolidinone (TMSO, 38.2 ml) and 0.02 mole of triethylamine p-toluenesulphonate (8.468 g). After stirring for 15 minutes, the mixture was heated under reflux for 120 minutes. Thereafter 0.1 mole of dimethylaniline p-toluene sulphonate (29.3 g) and 0.12 mole of thiourea (9.13 g) were added and heating was maintained for a further 60 minutes. Thereafter the mixture was concentrated at reduced pressure and water (100 ml) was added to the residue. The pH was adjusted to 8.5 in the presence of methylene chloride, the phenyl-pseudothio-hydantoin was filtered out and the water phase was decanted off. After further adjustment To pH 4.2, the mixture was filtered again to give 7-ADCA (14.9 g) with 70% yield. Identified by its IR spectrum, m.p. 232- 42 (d) and [α] D2 = 105.0° (C = 1%, 0.5 N HCL).
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[S:27][C:28]([CH2:32]O)=[C:29]([CH3:31])[N:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:32][C:28]3[S:27][C:26]([CH3:25])=[N:30][C:29]=3[CH3:31])=[CH:22][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc(C)c(CO)s1
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(O)cc3)cnc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C)c(COc2ccc(-c3cnc4c(C#N)cnn4c3C3CCCCC3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold mixture of 40 mg (0.13 mmol) of 7-cyclohexyl-6-(4-hydroxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 3 mL of tetrahydrofuran (THF) was added 74 mg (0.52 mmol) of (2,4-dimethyl-thiazol-5-yl)-methanol, 136 mg (0.52 mmol) of triphenylphosphine (PPh3), followed by 0.102 mL (0.52 mmol) of diisopropyl azodicarboxylate (DIAD) and the mixture was allowed to warm up to rt and stirred at rt overnight. The reaction mixture was then concentrated and the residue was chromatographed on silica gel (Biotage; 10% ethyl acetate in DCM) to give desired 7-cyclohexyl-6-[4-(2,4-dimethyl-thiazol-5-ylmethoxy)-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as indicated by 1H-NMR; LC-MS—calcd for C25H25N5OS [M++H]+: 444.18, found: 444.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)(C)C
Yield: 19.9 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 3.9 ml (0.036 mol) of t-butylamine in 30 ml of DMF were reacted affording a residue which was kugelrohr distilled at 133 Pa, pot temperature 126° C., giving 4.49 g. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent afforded 1.12 g of product as a white solid; mp 51.5°-53° C.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[C:10]([C:14]1[CH:15]=[C:16]([NH2:35])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].ClC(Cl)(Cl)COC(=O)NC1N(C2C=CC=C(SCCO)C=2)N=C(C(C)(C)C)C=1>>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:35][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1

Procedure:
The title compound was prepared starting from 2,2,2-trichloroethylchloroformate and Intermediate 39a by using an analogous procedure to that described for Intermediate 35c. LCMS (Method 4): Rt 3.85, m/z 536 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N>C1COCC1.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-amino-5-methoxy-benzoic acid (5.00 g, 30.0 mmol) in THF (50 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.50 g, 39.0 mmol), 1-hydroxybenzotriazole (4.50 g, 33.0 mmol) and 4-methylmorpholine (3.6 mL, 33.0 mmol) and the reaction mixture was stirred at room temperature for 1 hours. Then, 50% aqueous NH3 (8 mL, 105.0 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the product was extracted with ethyl acetate. Solvent was evaporated in vacuo and the residue was washed with ether to give 2-amino-5-methoxy-benzamide as a white solid. Yield: 2.62 g (53%).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2C=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>C(Cl)Cl.C1COCC1>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH2:48][CH3:49])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and ethylamine (0.19 mL, 0.37 mmol, 2.0M soln in THF). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (17 mg, 40%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH2:24])[CH2:21]2.[C:25]([C:29]1[N:33]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[CH3:41])[N:32]=[CH:31][C:30]=1[C:42](O)=[O:43])([CH3:28])([CH3:27])[CH3:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOCC>[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH:24][C:42]([C:30]1[CH:31]=[N:32][N:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=3[CH3:41])[C:29]=1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:43])[CH2:21]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: Cc1cc(Cl)ccc1-n1ncc(C(=O)O)c1C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)ccc1-n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1C(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (Intermediate#115) (515 mg, 2.68 mmol) was added in one portion to 2-Adamantanamine hydrochloride (420 mg, 2.24 mmol), 5-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (655 mg, 2.24 mmol), 1-Hydroxybenzotriazole (363 mg, 2.68 mmol) and N-Ethyldiisopropylamine (1.149 mL, 6.71 mmol) in DMF (10 mL). The resulting mixture was stirred at 20° C. for 18 hours. The reaction mixture was diluted with Et2O (100 mL), and washed sequentially with water (3×25 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford desired product N-(2-adamantyl)-1-(4-chloro-2-methyl-phenyl)-5-tert-butyl-pyrazole-4-carboxamide (860 mg, 90%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2O)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[C:1]([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2[Cl:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2ncc(C#N)c(O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc2ncc(C#N)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of 6-acetamido-4-hydroxyl-[1,5]naphthyridine-3-carbonitrile (1.0 g, 4.386 mmol) was heated at reflux in POCl3 (20 ml) under nitrogen for 5 hrs. After cooling, the solvent was removed by rotary evaporation. Ice water was added to the black residue, which was cooled (ice bath) and stirred for 1 hr. The mixture was warmed to room temperature and stirred at room temperature for 1 hr. The mixture was cooled with ice bath, and made basic with NH4OH. The aqueous layer was extracted with CH2Cl2. The combined extracts were washed with water, dried (Na2SO4) and concentrated to give the title compound as a dark blue solid (200 mg, 19%).
Reaction SMILES: [CH:1]1([C:7]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[CH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17](O)(=[O:19])[CH3:18].C(N)(=S)C.CC[O:27]CC>>[C:17]([O:16][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8](=[O:27])[CH3:9])(=[O:19])[CH3:18]
Reactant: CCOCC
Reactant: C#CC(O)(c1ccccc1)C1CCCCC1
Reactant: CC(=O)O
Agent: CC(N)=S
Product: CC(=O)OC(C(C)=O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
3-Cyclohexyl-3-hydroxy-3-phenylprop-1-yne (21.57 g, 0.10 mol) was added to 100 ml of glacial acetic acid. While the solution was stirred vigorously mercuric acetate (35.20 g, 0.11 mol) was added. The solution was stirred at room temperature for 72 hours and then thioacetamide (8.3 g, 0.11 mol) was added. The solution was stirred an additional 3 hours and 300 ml of ether was added. The reaction mixture was transferred to a separatory funnel and washed with water, saturated sodium bicarbonate solution, and again with water. The ether layer was dried over sodium sulfate and the ether removed under vacuum to afford the product as a white crystalline solid (18.36 g, 66.9%). Mp 81°-83° C. (from petroleum ether). 1H NMR (CDCl3) δ7.3(bs, 5H), 2.2(s, 3H), 1.9(s, 3H), 2.0-0.8(m, 11H).
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[CH:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=[CH:18]4)[CH:11]=2)[CH2:6][NH:5][CH2:4]1)[CH3:2].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:27]([N:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[CH:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=[CH:18]4)[CH:11]=2)[CH2:6]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: CCC1CNCc2ccc(C=Cc3ccc4cc(C#N)ccc4c3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1CN(Cc2ccccc2)Cc2ccc(C=Cc3ccc4cc(C#N)ccc4c3)cc21
Reaction time: 24 h

Procedure:
A solution of Example 49A (600 mg) in dichloromethane (25 mL) was treated sequentially with benzaldehyde (0.7 mL), sodium triacetoxyborohydride (1.3 g), and acetic acid (319 mg), stirred for 24 hours, diluted with dichloromethane, washed with 1M NaOH and brine, dried (MgSO4), filtered, and concentrated. The concentrate was crystallized from diethyl ether/hexanes to provide the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:32][CH2:33][CH3:34])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:31]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:47][C:9]1[C:8]2[N:31]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:32][CH2:33][CH3:34])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]3)=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCCn1c(CCOC)nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Reaction time: 0.75 h

Procedure:
A stirred solution of tert-butyl 4-{[2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (9.77 g, 20.8 mmol) in chloroform (175 mL) at room temperature was treated with mCPBA (55% pure, 6.54 g, 20.8 mmol). After 45 minutes, concentrated ammonium hydroxide (175 mL) was added, followed by p-toluenesulfonyl chloride (3.97 g, 20.8 mmol). The mixture was stirred for 62 hours, then the layers were separated and the aqueous layer was extracted with chloroform. The combined organic layers were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 1.5-12.5% CMA in chloroform) followed by recrystallization from acetonitrile to afford 6.3 g of tert-butyl 4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as tan crystals, mp 173-175° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C:15]=1[CH:16]([CH3:18])[CH3:17])=[O:10])C1C=CC=CC=1.O1CCCC1.CO.[H-].[OH-].[Li+]>O>[CH:16]([C:15]1[O:14][C:13]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:12][C:11]=1[C:9]([OH:10])=[O:8])([CH3:18])[CH3:17]
Reactant: CC(C)c1oc(-c2ccccc2)nc1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1oc(-c2ccccc2)nc1C(=O)O
Yield: 41.2 %

Procedure:
Solution of 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester (830 mg, 2.59 mmol) in a mix of tetrahydrofuran, methanol and water (3:1:1, 10 mL) was treated with lithium hydroxide monohydride (258 mg, 6.5 mmol) at room temperature for an hour. After the reaction was complete, solvent was removed. To the residue, water and dichloromethane were added, and white precipitate formed. After filtering off the solid, filtrate was collected and the phases were separated. The pH of the aqueous layer was adjusted to 1˜2 with dilute hydrochloride acid (1N). Then the aqueous layer was extracted with ethyl acetate three times. The ethyl acetate layers were collected, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-80% ethyl acetate in hexane for 20 min) gave 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid (247 mg, 41%) as a white solid. LCMS calcd for C13H13NO3 (m/e) 231, obsd 232 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH:20][C:21](=[O:23])[CH3:22])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=2)=[CH:6][CH:5]=1.ClC1C=C(C=CC=1)C(OO)=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][S:18]([C:14]1[N:13]=[C:12]([C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH:2]([NH:20][C:21](=[O:23])[CH3:22])[CH3:1])=[CH:9][CH:8]=2)[CH:17]=[CH:16][N:15]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccnc(S(C)=O)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.30 g (0.922 mmol) N-{1-methyl-2-[4-(2-methylsulfanyl-pyrimidin-4-ylethynyl)-phenyl]-ethyl}-acetamide (example 14.1) in 9 mL DCM is cooled down to 0° C. and charged with 0.27 g (1.10 mmol; 70% purity) 3-chloroperoxybenzoic acid. The mixture is stirred for 30 min at constant temperature. The mixture is poured onto sat. aq. NaHCO3 solution. The organic layer is separated, dried with Na2SO4 and filtered. The resulting mixture can be used directly used in the following reaction.
Reaction SMILES: C1C(C=O)=CC(Br)=CC=1C=O.O1C2C=CC(B(O)O)=CC=2OC1.NCCCNCCCNC(=O)OC(C)(C)C.[ClH:40].[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]3[CH:51]=[C:52]([CH2:66][NH:67][CH2:68][CH2:69][CH2:70][NH:71][CH2:72][CH2:73][CH2:74][NH2:75])[CH:53]=[C:54]([CH2:56][NH:57][CH2:58][CH2:59][CH2:60][NH:61][CH2:62][CH2:63][CH2:64][NH2:65])[CH:55]=3)=[CH:49][C:44]=2[O:43][CH2:42]1>>[Cl-:40].[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]3[CH:55]=[C:54]([CH2:56][NH2+:57][CH2:58][CH2:59][CH2:60][NH2+:61][CH2:62][CH2:63][CH2:64][NH3+:65])[CH:53]=[C:52]([CH2:66][NH2+:67][CH2:68][CH2:69][CH2:70][NH2+:71][CH2:72][CH2:73][CH2:74][NH3+:75])[CH:51]=3)=[CH:49][C:44]=2[O:43][CH2:42]1.[Cl-:40].[Cl-:40].[Cl-:40].[Cl-:40].[Cl-:40]
Reactant: NCCCNCCCNCc1cc(CNCCCNCCCN)cc(-c2ccc3c(c2)OCO3)c1
Reactant: Cl
Agent: CC(C)(C)OC(=O)NCCCNCCCN
Agent: O=Cc1cc(Br)cc(C=O)c1
Agent: OB(O)c1ccc2c(c1)OCO2
Product: [Cl-]
Product: [NH3+]CCC[NH2+]CCC[NH2+]Cc1cc(C[NH2+]CCC[NH2+]CCC[NH3+])cc(-c2ccc3c(c2)OCO3)c1

Procedure:
Example 46 was prepared in a similar fashion to Example 45 (CZ-58) from 5-bromoisophthaldehyde, benzo[d][1,3]dioxol-5-ylboronic acid, and tert-butyl (3-((3-aminopropyl)amino)propyl)carbamate. N1,N1′-((5-(benzo[d][1,3]dioxol-5-yl)-1,3-phenylene)bis(methylene))bis(N3-(3-aminopropyl)propane-1,3-diamine), hydrochloride salt: 1H NMR (500 MHz, D2O) δ 7.72 (s, 2H), 7.49 (s, 1H), 7.15 (s, 2H), 6.93 (d, J=8.5 Hz, 1H), 5.95 (s, 2H), 4.30 (s, 4H), 3.21-3.12 (m, 8H), 3.05 (t, J=8.0 Hz, 4H), 2.17-2.02 (m, 8H). 13C NMR (125 MHz, D2O) δ 148.1, 147.6, 142.3, 133.3, 132.2, 130.8, 129.7, 129.6, 129.4, 121.1, 109.0, 107.5, 101.6, 51.0, 44.8, 44.8, 44.4, 36.6, 23.9, 22.8.