Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[N+:29]([O-:59])([O:31][C@@H:32]1[CH:49]2[C@:44]([CH3:50])([CH2:45][CH2:46][CH2:47][CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38]24[O:55][CH2:56][CH2:57][O:58][C:37]2([O:54][CH2:53][CH2:52][O:51]4)[CH2:36]3)[CH2:33]1)=[O:30]>>[N+:29]([O-:59])([O:31][C@H:32]1[CH:49]2[C@:44]([CH3:50])([CH2:45][CH2:46][CH2:47][CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38]24[O:51][CH2:52][CH2:53][O:54][C:37]2([O:58][CH2:57][CH2:56][O:55]4)[CH2:36]3)[CH2:33]1)=[O:30]
Reactant: C[C@]12CCCCC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Agent: C[C@]12CCCCC1[C@H](O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1[C@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 50 %

Procedure:
17,17-Bis(ethylendioxy)androstane-6β-yl nitrate was prepared in 50% yield from 3,3:17,17-bis(ethylendioxy)androstan-6β-ol following the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)androstane-6α-yl nitrate (Prepn. 1). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.16 (m, 1H), 3.93-3.76 (m, 8H), 2.20-0.77 (m, 20H), 1.00 (s, 3H), 0.85 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[N:14]=[C:13]([CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:24][C:20]=3[C:19](=[O:31])[N:18]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:17]2=[O:38])[CH:12]=[N:11]1)[CH3:9].[CH2:39]([O:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:49]2[C:48]([C:54]3[CH:62]=[CH:61][C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=3)=[N:47][C@@H:46]3[CH2:63][CH2:64][S:65][CH2:66][C@@H:45]3[C:44]=2[CH:43]=1)[CH3:40].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.O>[CH2:39]([O:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:49]2[C:48]([C:54]3[CH:55]=[CH:56][C:57]([C:58]([N:35]4[CH2:36][CH2:37][CH:32]([N:18]5[C:19](=[O:31])[C:20]6[S:24][C:23]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)=[CH:22][C:21]=6[N:16]([CH2:15][C:13]6[CH:12]=[N:11][N:10]([CH2:8][CH3:9])[N:14]=6)[C:17]5=[O:38])[CH2:33][CH2:34]4)=[O:59])=[CH:61][CH:62]=3)=[N:47][C@@H:46]3[CH2:63][CH2:64][S:65][CH2:66][C@@H:45]3[C:44]=2[CH:43]=1)[CH3:40]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=S(=O)([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
To a suspension of 1-[(2-ethyl-2H-1,2,3-triazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (300 mg; compound B45), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (217 mg; compound C10), EDCI (104 mg) and HOBT hydrate (74 mg) in DCM (10 ml) DIPEA (0.24 ml) is added. After 14 h at RT water and aqueous potassium hydrogen sulfate solution (10% w/w) are added and the mixture is extracted with DCM. The combined organic layers are dried (sodium sulfate) and concentrated under reduced pressure. The residue is purified by twofold flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC to afford the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].Br[CH2:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)=[O:33]>O1CCCC1>[C:34]1([C:32]([CH2:31][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:4][CH:3]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]2=[O:1])=[O:33])[S:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(CBr)c1cccs1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1cccs1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) was dissolved in tetrahydrofuran (10 ml), 60% sodium hydride (0.16 g) was added thereto under argon atmosphere, and the mixture was stirred for 30 minutes at room temperature. A solution of 2-bromoacetylthiophene (0.99 g) in tetrahydrofuran (1 ml) was added to the resultant mixture, stirred for 2 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate, the organic layer was washed succesively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 1.01 g of the titled compound (Yield: 76%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].Br[CH2:26][C:27](=[O:41])[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:16]([N:15]1[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=[C:6]1[CH:2]([NH:1][CH2:26][C:27](=[O:41])[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH:3]([CH3:5])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(NCC(=O)CCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A suspension of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (1.0 g, 2.93 mmol), 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (867 mg., 2.93 mmol, prepared as described in WO 89/10360), and potassium carbonate (405 mg, 2.93 mmol) in DMF (14 mL) was stirred at room temperature for 80 minutes. The reaction was diluted with water and the resulting white solid (1.6 g) was used in the subsequent step without further purification.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([CH3:33])[CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:32]=[CH:31][C:21]3[NH:22][C:23]([CH2:25][C:26](OCC)=[O:27])=[N:24][C:20]=3[CH:19]=2)[CH2:14]1.[NH2:34][C:35]1[C:36]([C:41]#[N:42])=[N:37][CH:38]=[CH:39][CH:40]=1>C1COCC1>[NH2:42][C:41]1[C:36]2[C:35](=[CH:40][CH:39]=[CH:38][N:37]=2)[NH:34][C:26](=[O:27])[C:25]=1[C:23]1[NH:22][C:21]2[CH:31]=[CH:32][C:18]([N:15]3[CH2:16][CH2:17][CH:13]([N:12]([CH3:11])[CH3:33])[CH2:14]3)=[CH:19][C:20]=2[N:24]=1
Reactant: CCOC(=O)Cc1nc2cc(N3CCC(N(C)C)C3)ccc2[nH]1
Reactant: N#Cc1ncccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc3[nH]c(-c4c(N)c5ncccc5[nH]c4=O)nc3c2)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
LiHMDS (3.6 eq) was added to ethyl {5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}acetate (1.0 eq) and 3-aminopyridine-2-carbonitrile (J. Org. Chem. 1958, 1616-1617; 1.0 eq) in THF at 0° C. The reaction was stirred overnight and then heated at 40° C. for 3 hours. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a green solid. The crude material was washed successively with CH2Cl2 and MeOH, and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 390.2 (MH+), Rt 1.79 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([C:34]1[S:38][C:37]([C:39](O)=[O:40])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39]([C:37]4[S:38][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=4)=[O:40])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(S(C)(=O)=O)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (44.3 mg, 0.21 mmol)
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[F:4][C:5]1([F:37])[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[C:28]([O:33][CH3:34])=[N:29][CH:30]=[CH:31][CH:32]=5)[N:20]4[N:19]=3)=[C:13]([O:35][CH3:36])[CH:12]=2)[CH2:9][CH2:8][NH:7][CH2:6]1>>[F:37][C:5]1([F:4])[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[C:28]([O:33][CH3:34])=[N:29][CH:30]=[CH:31][CH:32]=5)[N:20]4[N:19]=3)=[C:13]([O:35][CH3:36])[CH:12]=2)[CH2:9][CH2:8][N:7]([CH2:1][CH2:2][OH:3])[CH2:6]1
Reactant: C1CO1
Reactant: COc1cc(C2CCNCC2(F)F)ccc1Nc1ncc2ccc(-c3cccnc3OC)n2n1
Product: COc1cc(C2CCN(CCO)CC2(F)F)ccc1Nc1ncc2ccc(-c3cccnc3OC)n2n1

Procedure:
Ethylene oxide and (±)-[4-(3,3-difluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (Example 12, 68 mg) were converted to the title product by a procedure similar to the one described for Example 8 to give a yellow foam (51 mg, 68% yield). 1H NMR (CDCl3): 8.72 (s, 1H), 8.48 (d, J=7.4 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.24 (d, J=4.3 Hz, 1H), 7.51 (s, 1H), 7.14 (d, J=3.6 Hz, 1H), 7.08 (m, 1H), 6.84 (m, 2H), 4.02 (s, 3H), 3.92 (s, 3H), 3.68 (m, 2H), 3.25 (m, 1H), 3.10 (m, 1H), 2.90 (m, 1H), 2.74 (m, 1H), 2.65 (m, 1H), 2.46 (dd, J=28.3 (F-H vic. coupling), 11.7 Hz, 1H), 2.27 (m, 3H), 1.90 (m, 1H); LC/MS (ESI+): 510.54 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[NH:14][CH2:15][C:16]([NH:18][CH:19]2[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:30][C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:32])[NH:14][CH2:15][C:16]([NH:18][CH:19]2[CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Reaction time: 1 h

Procedure:
To a solution of the compound (1.92 g), which had been obtained in (1), in anhydrous dichloromethane (10 ml), trifluoroacetic acid (5 ml) was added under ice cooling. The resulting mixture was stirred for one hour, followed by concentration under reduced pressure. The residue was washed with hexane-ether, followed by evaporation of the solvent, whereby 2.78 g of the title target compound were obtained. The product was provided for the subsequent step without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15](C3CCCCO3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:25][C:40]([C:36]4[O:35][CH:39]=[CH:38][CH:37]=4)=[O:41])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg) in DCM (1 ml) was added DIPEA (131 μl) followed by 2-furancarbonyl chloride (39 mg) (available from ABCR) and the mixture stirred at RT for 1 h, then the solvent was removed. To a mixture of the residue in methanol (2 ml) was added 4M hydrochloric acid in 1,4-dioxane (2 ml) and the mixture stirred at RT for 2 h. Purification of the residue by mass directed preparative HPLC (Method A), followed by freeze drying gave the title compound as an off white solid (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH2:30][CH:31]2[NH:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:36]2[CH:31]([CH2:30][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH2:32][CH2:33][CH:34]([OH:37])[CH2:35]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: OC1CCC(CN2CCCC2)NC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CC(O)CCC1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
A solution of 3,4-dichlorophenylacetic acid (0.64 g) in dry dichloromethane (15 ml) was treated with 1,1'-carbonyldiimidazole (0.51 g) portionwise over a 5 minute period. The mixture was stirred at ambient temperature for 40 min and was added to a solution of the product of stage (ii) (0.55 g) in dichloromethane (20 ml). The reaction mixture was stirred at ambient temperature for 18 h, diluted with dichloromethane (50 ml) and washed with aqueous sodium carbonate solution (2M; 2×10 ml). The organic extract was dried, filtered, and evaporated in vacuo to give an oily residue (1.1 g). The residue was purified by flash chromatography using dichloromethane methanol/ammonia (200:8:1) as eluent to give the title compound as an oil (0.32 g). T.l.c. Silica(dichloromethane/methanol/ammonia 150:8:1) Rf 0.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(CCO)C>[Cu]I.[Cu].O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: OC1CCNC1
Agent: [Cu]
Agent: [Cu]I
Agent: CN(C)CCO
Solvent: C1COCCO1
Product: OC1CCN(c2ccc(F)cc2)C1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, a 1,4-dioxane suspension of 1-fluoro-4-iodobenzene (2.00 g, 9.01 mmol), pyrrolidin-3-ol (785 mg, 9.01 mmol), potassium phosphate (3.83 g, 18.0 mmol), copper (I) iodide (343 mg, 1.80 mmol), copper (114 mg, 1.80 mmol), and N,N-dimethylaminoethanol (100 mg) was stirred at 90° C. for 1 day and at 110° C. for 5 hours. After completion of the reaction, the reaction solution was filtered with Celite and the filtrate was concentrated under reduced pressure. To the residue, water was added and extraction with ethyl acetate from the resultant mixture was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:41]=[CH:40][C:32]3[N:33]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[S:35][C:31]=3[CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.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>[OH:20][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:4]2[CH:3]=[C:2]([C:29]3[CH:41]=[CH:40][C:32]4[N:33]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[S:35][C:31]=4[CH:30]=3)[CH:7]=[N:6][CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)[CH3:19]
Reactant: CC(O)c1ccc(S(=O)(=O)Nc2cncc(Br)c2)cc1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
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: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(-c3cncc(NS(=O)(=O)c4ccc(C(C)O)cc4)c3)cc2s1
Temperature: 100 °C
Yield: 15.7 %

Procedure:
A mixture of N-(5-bromopyridin-3-yl)-4-(1-hydroxyethyl)benzenesulfonamide (0.120 g, 0.34 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.11 g, 0.34 mmol), tetrakis(triphenylphosphine)palladium (0.019 g, 0.017 mmol) in 1 ml of dioxane and 1 ml of aq. 2M sodium carbonate was heated under microwave (CEM) at 120 W, 100° C. for 20 min. Then, the resultant was diluted with DCM and water. The organic layer was separated, dried and concentrated. The residue was purified by HPLC (5-60% CH3CN in water gradient) to give a light yellow solid (25 mg, 16%). MS (ESI pos. ion) Found m/z: 469, (M+H)+.
Reaction SMILES: O1CCCC1.B.CO.[Br:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([C:20](O)=[O:21])([CH2:13]3)[CH2:11]1)[CH2:17]2>O1CCCC1>[Br:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([CH2:20][OH:21])([CH2:13]3)[CH2:11]1)[CH2:17]2
Reactant: O=C(O)C12CC3CC(CC(Br)(C3)C1)C2
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCC12CC3CC(CC(Br)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 ml round-bottomed flask, 3-bromoadamantane-1-carboxylic acid (7.89 g) was dissolved in tetrahydrofuran (30 mL). Borane tetrahydrofuran complex (1M in hexane, 60 mL) was added slowly. The mixture was stirred at room temperature overnight. Methanol (20 mL) was added to the solution slowly. After removal of the solvents, methanol (5 mL) was added to the oily residue. Removal of the solvent provided the title compound.
Reaction SMILES: [N:1]1([C:60](OC(C)(C)C)=O)[CH2:59][CH2:58][CH2:57][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:38]([NH:40][C@H:41]([C:46]([NH:48][C@H:49]([C:54]([NH2:56])=[O:55])[CH2:50][CH2:51][S:52][CH3:53])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:29][NH:30]C(OC(C)(C)C)=O)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:60][CH2:59][CH2:58][CH2:57][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:38]([NH:40][C@H:41]([C:46]([NH:48][C@H:49]([C:54]([NH2:56])=[O:55])[CH2:50][CH2:51][S:52][CH3:53])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:29][NH2:30])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CN)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-Phe-LDap(Boc)-LeuNHNH2 (607 mg.) and HMetNH2 (150 mg.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-LDap(Boc)-Leu-MetNH2 in 67% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-LDap(Boc)-Leu-MetNH2 (430 mg.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-LDap-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 95% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[OH-].[Na+].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14]>CS(C)=O>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][O:5][CH2:14][CH2:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: OCC(CO)(CO)CO
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCOCC(CO)(CO)CO
Temperature: 80 °C
Yield: 42 %

Procedure:
To DMSO (100 mL) was added pentaerythritol 1 (68 g, 0.5 mol); the heterogeneous suspension was heated to 80° C. until the system became clear, then aqueous NaOH (4 g of NaOH in 9 mL of H2O) was added in one portion, tert-butyl acrylate (87 mL, 0.6 mol) was added to the solution dropwise, and vigorous stirring continued overnight at 80° C. After cooling, the solution was extracted with EtOAc. The combined organic phase was washed with H2O and brine, concentrated through rotary evaporation, and the residue was subjected to silica gel chromatography using CH2Cl2/MeOH as the eluent to give 2 (54.3 g, 0.21 mol, 41% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 3.63 (br, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.52 (s, 6H), 3.37 (s, 2H), 2.38 (t, J=5.0 Hz, 2H), 1.37 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 171.7, 81.2, 72.1, 67.2, 63.6, 45.3, 36.1, 28.1; MS (ESI) m/z 209 (M−tBu+2H)+, 265 (M+H)+, 287 (M+Na)+; HRMS (ESI) calcd for C12H25O6 265.1651 (M+H)+, 209.1025 [M−tBu+2H]+. found 265.1646, 209.1026, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[N:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(C(F)(F)F)=O.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3ncccc23)CC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CCCN3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of 4-pyrido[2,3-d]pyrimidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (0.24 g, 0.76 mmol) in MeOH (10 mL) and TFA (1 mL) was added PtO2 (10 mg). The mixture was stirred under H2 (1 atm) at room temperature overnight. The catalyst was filtered off and the solvent was removed. The residue was subject to column chromatography, eluted by DCM/MeOH (20:1) to afford 4-(5,6,7,8-Tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.15 g, 62%). 1H NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 5.92 (s, 1H), 3.50 (m, 4H), 3.40 (m, 2H), 3.25 (m, 4H), 2.55 (m, 2H), 1.85 (m, 2H), 1.48 (s, 9H). MS (APCI+) [M+H]+320.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O.CCOC(C)=O>CN(C=O)C.[Cu]Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:17]#[C:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Cu]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ncc(Cl)cc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 30 %

Procedure:
A solution of 3-bromo-5-chloro-2-pyridinamine (414 mg, 2.0 mmol), phenyl acetylene (225 mg, 2.2 mmol), copper (I) chloride (16 mg, 0.16 mmol), triethylamine (555 μl, 4.0 mmol) and dichlorobis(triphenylphosphine)palladium (II) (32 mg, 0.05 mmol) in DMF (0.5 ml) in a teflon pressure vessel was heated in a microwave (full power) for 30 sec. allowed to cool to RT and reheated for a further 30 sec. After cooling to RT, the reaction mixture was partioned between water—EtOAc, and the organic phase washed with sat. brine, dried oxer MgSO4, and concentrated. Purification by column chromatography on silica gel eluting with methylene chloride-methanol (99:1) and subsequent crystallisation from hexane gave the title compound as a yellow solid (130 mg, 0.6 mmol):