Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].FC(F)(F)C(O)=O.[CH3:64][C:65]1[CH:66]=[N:67][C:68]2[NH:69][C:70]3[CH:71]=[N:72][CH:73]=[C:74]([CH:87]=3)[CH2:75][CH2:76][C:77]3[CH:85]=[C:81]([NH:82][C:83]=1[N:84]=2)[CH:80]=[CH:79][C:78]=3[NH2:86]>CN(C)C=O.C(N(CC)C(C)C)(C)C>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:86][C:78]3[CH:79]=[CH:80][C:81]4[NH:82][C:83]5[N:84]=[C:68]([NH:69][C:70]6[CH:71]=[N:72][CH:73]=[C:74]([CH:87]=6)[CH2:75][CH2:76][C:77]=3[CH:85]=4)[N:67]=[CH:66][C:65]=5[CH3:64])=[O:18])[CH2:13][CH2:14]2)=[O:8])[CH:3]=1
Reactant: Cc1cnc2nc1Nc1ccc(N)c(c1)CCc1cncc(c1)N2
Reactant: Cc1cc(C(=O)N2CCC(CC(=O)O)CC2)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(C)c(n3)N4)CC2)no1
Reaction time: 8 h
Yield: 3.4 %

Procedure:
A solution of {1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}acetic acid (4.8 mg, 0.019 mmol) (prepared in Example C49, step I), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (19 mg, 0.050 mmol) in N,N-dimethylformamide (0.2 mL) and N,N-diisopropylethylamine (7.6 uL) was stirred for 15 minutes. A solution of 6-methyl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) (6.0 mg, 0.019 mmol) (prepared in Example C29, step C) in N,N-dimethylformamide (0.1 mL) and was added to the previous solution and was stirred overnight. The reaction mixture was purified by preparative HPLC (pH 2) to give the desired product (0.5 mg, 19%). LCMS for C30H33N8O3 (M+H)+: m/z=553.2. 1H NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 9.38 (s, 1H), 9.34 (s, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.00 (dd, J=8.3, 2.2 Hz, 1H), 6.41 (dd, J=8.1, 0.8 Hz, 1H), 4.42 (m, 4H), 3.86 (m, 4H), 2.90-3.10 (m, 6H), 2.10-2.30 (m, 4H), 2.66 (s, 3H).
Reaction SMILES: C(OC(C)C(=O)[O:7][CH2:8][CH:9]1[O:13][CH:12]([N:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[N:16][C:15]2=[O:24])[CH2:11][CH2:10]1)(=O)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(O)C>[C@@H:12]1([N:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][C:15]2=[O:24])[O:13][C@H:9]([CH2:8][OH:7])[CH2:10][CH2:11]1
Reactant: CC(=O)Nc1ccn(C2CCC(COC(=O)C(C)OC(C)=O)O2)c(=O)n1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Product: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
A solution of 20.7 g of the product from Example 14 in 100 mL of ethanol was treated with 10.0 mL of Triton B (N-benzyltrimethyl-ammonium hydroxide), and the mixture was stirred at room temperature overnight. The mixture was concentrated to 20 ml, cooled to 0° C., and the product was collected by filtration. It was washed with 10 mL of cold ethanol to give 4.48 g of 2',3'-dideoxycytidine, mp 215°-218° C., as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:15]1([O:14][CH2:13][CH2:12][S:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:23])[C:3]([OH:24])=[O:2])=[CH:10][CH:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C(=O)c1ccc(SCCOC2CCCCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(SCCOC2CCCCCCC2)cc1
Yield: 93.3 %

Procedure:
A solution of 4-[[2-(cyclooctyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid methyl ester (0.96 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (3.5 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from diethyl ether-hexane provided 0.86 g of purified 4-[[2-(cyclooctyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid as a yellow solid, mp 84°-85° C.
Reaction SMILES: C(C1NC2C3[C@@H]1C[C@@H]1C(C=3C=CC=2)=C[C@H](N)CN1CCC)C.[CH2:23]([CH:25]1[NH:39][C:38]2[C:40]3[C@@H:26]1[CH2:27][C@@H:28]1[C:33]([C:34]=3[CH:35]=[CH:36][CH:37]=2)=[CH:32][C@H:31]([NH:41][CH:42]=[O:43])[CH2:30][N:29]1[CH2:44][CH2:45][CH3:46])C>>[CH3:23][C:25]1[NH:39][C:38]2[C:40]3[C:26]=1[CH2:27][C@@H:28]1[C@@H:33]([C:34]=3[CH:35]=[CH:36][CH:37]=2)[CH2:32][C@H:31]([NH:41][CH:42]=[O:43])[CH2:30][N:29]1[CH2:44][CH2:45][CH3:46]
Reactant: CCCN1C[C@@H](NC=O)C=C2c3cccc4c3[C@H](C[C@H]21)C(CC)N4
Agent: CCCN1C[C@@H](N)C=C2c3cccc4c3[C@H](C[C@H]21)C(CC)N4
Product: CCCN1C[C@@H](NC=O)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21

Procedure:
from 9,10-didehydro-2,3beta-dihydro-2-ethyl-6-n-propyl-8alpha-ergolinylamine the N-(9,10-didehydro-2,3beta-dihydro-2-ethyl-6-n-propyl-8alpha-ergolinyl)-formamide, yield 71%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1(C)[C:36](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:32]([CH3:36])=[CH2:31])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=C(C)c1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Yield: 74.9 %

Procedure:
A mixture of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.080 g, 0.166 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.084 g, 0.499 mmol), K2CO3 (0.046 g, 0.332 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.014 g, 0.017 mmol) in dioxane (3 mL) and H2O (0.5 mL) was stirred at 90° C. for 15 h. The solvent was removed in vacuo and the residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-(7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.055 g, 75%). LC/MS (Table 1, Method 2) Rt=1.240 min.; MS m/z: 443 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Br.Br[CH:8]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2)=O.C(N(CC)CC)C>C(#N)C>[CH2:16]1[C:17]2[C:13](=[CH:12][C:11]([C:9]3[N:5]=[C:3]([NH:2][CH3:1])[S:4][C:8]=3[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: CNC(N)=S
Reactant: O=C(c1ccc2c(c1)CCC2)C(Br)c1cccnc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1nc(-c2ccc3c(c2)CCC3)c(-c2cccnc2)s1
Reaction time: 2 h
Yield: 80 %

Procedure:
In 40 ml of acetonitrile was dissolved 661 mg. of N-methyl thiourea. In the solution was suspended 2.9 g of 2-bromo-1-(5-indanyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added dropwise slowly 1 ml of triethylamine. The mixture was then stirred for 2 hours at refluxing temperature, followed by being left standing for cooling. The solvent was then evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and, then, the solvent was evaporated off. Recrystallization was conducted from ethyl acetate-isopropylether afforded 1.8 g (80%) of 4-(5-indanyl)-2-methylamino-5-(3-pyridyl)-1,3-thiazole, m.p. 169°-170° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCCC1>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:24])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCOc1cc(-c2ccccc2)c2ccccc2n1
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(CCCCCOc1cc(-c2ccccc2)c2ccccc2n1)N1CCCC1

Procedure:
To a solution of 5 g of 6-[(4-phenyl-2-quinolyl)oxy]hexanoic acid in 120 cc of tetrahydrofuran is added 2.9 g of 1,1'-carbonyldiimidazole. The mixture is stirred for 2 hours to 50° C. After cooling, 1.3 g of pyrrolidine is added and the mixture is stirred at room temperature overnight. The tetrahydrofuran is removed in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate solution is washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue is then purified by flash chromatography on silica gel (30-60mm; eluent: 3:7 cyclohexane/ethyl acetate) to give 1-[6-(4-phenyl-2-quinolyloxy)hexanoyl]pyrrolidine as a white solid m.p.=52°-54° C.)
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:19]([CH2:40][OH:41])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([O:50][C@H:51]1[C@@H:63]([O:64][C:65](=[O:72])[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C@H:62]([O:73][C:74](=[O:81])[C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[C@@H:61]([CH2:82][O:83][C:84](=[O:91])[C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[O:60][C@@H:52]1OC(=N)C(Cl)(Cl)Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:19]([CH2:40][O:41][C@H:52]2[O:60][C@H:61]([CH2:82][O:83][C:84](=[O:91])[C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)[C@@H:62]([O:73][C:74](=[O:81])[C:75]3[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=3)[C@H:63]([O:64][C:65](=[O:72])[C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[C@@H:51]2[O:50][C:42](=[O:49])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(O[C@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)C(Cl)(Cl)Cl
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask was added 2-azidoethyl 2,3,4-tri-O-benzoyl-α-D-mannopyranoside (720 mg, 1.282 mmol), 2,3,4,6-tetra-O-benzoyl-1-O-(2,2,2-trichloroethanimidoyl)-α-D-mannopyranose (1.14 g, 1.539 mmol) and 4 Å molecular sieves (300 mg). To the above mixture was added CH2Cl2 (10 mL). The reaction mixture was cooled to -78° C. To the above mixture was added TMSOTf (23.2 μL, 0.128 mmol). The mixture was allowed to gradually warm to 0° C. and stirred for 30 min. The reaction was then quenched with sat. NaHCO3, and the mixture was filtered through a pad of Celite. The filtrate was diluted with CH2Cl2 (20 mL), washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (80 g), eluting with 0-100% EtOAc in hexanes, to give the title product. LC-MS Method A: m/e=1157.64 [M+18] and 1163.52 [M+Na]; Rt=3.01 min. 1H NMR (CDCl3) δ 7.2-8.3 (m, 25H), 6.0 (t, 1H), 5.8 (t, 1H), 5.7 (m, 2H), 5.4 (s, 1H), 5.38 (m, 1H), 5.2 (s, 1H), 4.7 (dd, 1H), 4.6 (dd, 1H), 4.45 (m, 1H), 4.35 (dd, 1H), 3.9-4.0 (m, 2H), 3.8 (m, 2H), 3.7 (m, 1H), 3.4 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(O[I:20](C1C=CC=CC=1)OC(=O)C)(=O)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[I:20][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:2][CH:3]=1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: O=C(O)CCCCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCCCc1ccc(I)cc1
Reaction time: 2 h
Yield: 129.1 %

Procedure:
5-Phenylpentanoic acid (50.0 g, 0.28 mol), iodine (37.77 g, 0.149 mol) and (diacetoxyiodo)benzene (48.0 g, 0.149 mol) are suspended in a mixture of glacial acetic acid (500 mL) and acetic anhydride (500 mL). Concentrated sulfuric acid (2 mL) is added and the suspension stirred for 2 h in the dark, during which the red colour fades. The solvent is removed under reduced pressure until approximately 80 ml remained, and the residue poured into ice-water (1 L) containing sodium metabisulfite (8 g). the resulting precipitate is stirred for 30 min, and then filtered. The crude product is recrystallised from ethanol/water, and then from acetic acid/water to afford the product (58.5 g). NMR showed the expected signals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1([CH2:18][O:19][CH3:20])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])[CH3:8].[Cl:21][C:22]1[CH:23]=[C:24]([C:33]2[O:37][N:36]=[C:35]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44]Cl)=[CH:40][CH:39]=3)[N:34]=2)[CH:25]=[CH:26][C:27]=1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1([CH2:18][O:19][CH3:20])[CH2:13][CH2:14][N:15]([CH2:44][C:41]2[CH:40]=[CH:39][C:38]([C:35]3[N:34]=[C:33]([C:24]4[CH:25]=[CH:26][C:27]([CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[C:22]([Cl:21])[CH:23]=4)[O:37][N:36]=3)=[CH:43][CH:42]=2)[CH2:16][CH2:17]1)=[O:11])[CH3:8]
Reactant: ClCc1ccc(-c2noc(-c3ccc(C4CCCC4)c(Cl)c3)n2)cc1
Reactant: CCOC(=O)C1(COC)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COC)CCN(Cc2ccc(-c3noc(-c4ccc(C5CCCC5)c(Cl)c4)n3)cc2)CC1
Temperature: 67.5 °C

Procedure:
Potassium carbonate (0.28 g, 0.002 mol) and 4-methoxymethylpiperidine-4-carboxylic acid ethyl ester (0.4 g, 0.002 mol) are added to a solution of 5-(3-Chloro-4-cyclopentylphenyl)-3-(4-chloromethyl-phenyl)-[1,2,4]oxadiazole (0.5 g, 0.0013 mol) in N,N-dimethylformamide (15 mL). The reaction mixture is heated at 65-70° C. for 2 hours. Removal of solvent gives a crude residue which is purified by column chromatography (silica gel 230-400 mesh, toluene:ethyl acetate 4:1) to give 1-{4-[5-(3-chloro-4-cyclopentylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4-methoxy methyl piperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[C:11]([O:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH:34]3[O:38][CH2:37][CH2:36][O:35]3)[CH:28]=2)[N:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[O:38]1[CH2:37][CH2:36][O:35][CH:34]1[C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([CH3:33])[CH:30]=1)[O:26][C:11]1[NH:10][C:9](=[O:8])[NH:14][C:13](=[O:15])[C:12]=1[CH:23]([CH3:25])[CH3:24]
Reactant: Cc1cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)cc(C2OCCO2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)cc(C2OCCO2)c1
Reaction time: 3 h
Yield: 88 %

Procedure:
2,4-Bis-benzyloxy-6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-pyrimidine (1.56 g, 3.04 mmol) in anhydrous THF (20 ml) was stirred in the presence of 10% palladium on carbon (58 mg) under an atmosphere of hydrogen. After 3 hr., the mixture was filtered through a celite pad and the pad was washed with methanol. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (4:1)) to afford 889 mg (89%) of a white solid. m.p. 201-203° C.; 1H NMR (200 MHz, CDCl3) δ 1.20 (6H, d, J=7.2 Hz), 2.37 (3H, s), 3.09 (1H, m), 4.02-4.15 (4H, m), 5.73 (1H, s), 6.80 (1H, s), 6.99 (1H, s), 7.16 (1H, s), 8.80 (1H, s), 9.19 (1H, s); m/z (LC/Mass, EI) 333 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]([CH3:25])[CH3:24])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CN(C)c1ccccc1Br
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2N(C)C)CCN(C)C1
Temperature: 25 °C
Yield: 6.3 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), (2-bromo-phenyl)-dimethyl-amine (600 mg, 3 mmol), K3PO4 (636 mg, 3 mmol), L-Proline (69 mg, 0.6 mmol) and CuI (57 mg, 0.3 mmol) in dry DMF (4 mL) was stirred at 150° C. for 16 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by column chromatography using neutral alumina and 10% EtOAc-Hexane followed by reverse phase HPLC purification to yield [2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-phenyl]-dimethyl-amine (20 mg). 1H NMR (TFA salt, CD3OD) d (ppm): 7.50 (m, 1H), 7.38 (m, 2H), 7.18 (m, 2H), 7.0 (m, 2H), 4.75 (d, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.58 (m, 1H), 3.15 (s, 3H), 3.0 (m, 1H), 2.70 (m, 1H), 2.56 (s, 6H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29][CH2:43][CH2:44][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCN1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1=C(C(=O)OCCN2CCCC2)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg (0.1 mmol) of the compound of Example 47 in 0.3 ml dry dimethylformamide are added 48.6 mg (0.3 mmol) N,N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is evaporated off in vacuo. To the residue are added 0.5 ml (492 mg, 4.28 mmol) 1-(2-hydroxyethyl)pyrrolidin and 10 μl (0.07 mmol) triethylamine. The reaction mixture is stirred at 100° C. for one hour. Then the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH:22]=[O:23])[CH2:21][CH2:20][CH2:19]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(CO)CCC3)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=O)CCC3)cc2c1
Reaction time: 1 h

Procedure:
To a solution of 2-(3-Ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-cyclobutyl)-2-methylsulfanyl-acetamide (310 mg) in CH2Cl2 (30 ml) was added solid Dess Martin periodinane (480 mg) at room temperature, under nitrogen atmosphere. The mixture was stirred at the same temperature during 1 hour, then poured into sat aq NaHCO3 and extracted with CH2Cl2 (2×15 ml). The organic phase was separated and washed with aq Na2S2O3 and sat. aq. NaCl then dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. The crude compound (250 mg) as yellow oil, was used for the next step without purification.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:28]=1)[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: O=C(c1ccc(CCl)cc1)N1CCCC1
Reactant: CCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CCC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (1.4 g) in anhydrous tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.3 mL). The mixture was stirred at 0° C. for 45 minutes and then a solution of (4-chloromethylphenyl)pyrrolidin-1-ylmethanone (2.0 g) in tetrahydrofuran (10 mL) was added and the resulting mixture heated at 70° C. for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 by volume) to afford title compound, 1.1 g.