Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH:14]1([CH2:17][N:18]2[C:26]3[N:25]=[C:24]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][CH3:35])=[CH:30][CH:29]=4)[NH:23][C:22]=3[C:21](=[O:36])[N:20]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[C:19]2=[O:45])[CH2:16][CH2:15]1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH:14]1([CH2:17][N:18]2[C:26]3[N:25]=[C:24]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([N:34]([CH3:35])[C:5](=[O:7])[C:4]5[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[N:11][C:3]=5[O:2][CH3:1])=[CH:32][CH:33]=4)[NH:23][C:22]=3[C:21](=[O:36])[N:20]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[C:19]2=[O:45])[CH2:16][CH2:15]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: COc1ccc(C(=O)O)c(OC)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)c(OC)n1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 2,6-dimethoxynicotinic acid (Aldrich) was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 1 equivalent of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and excess triethylamine and a catalytic amount of 4-dimethylaminopyridine were added as the final reagents to the reaction mixture. The product was purified by chromatography using silica gel eluted with 9:1 ethyl acetate/hexanes followed by crystallization from acetonitrile. MS, m/z(M+)=599.2417.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].FC(F)(F)C([O-])=O.[CH3:25][C:26]1[C:31](=[O:32])[N:30]([C:33]2[CH:34]=[C:35]([CH:37]=[C:38]([N:40]3[C:44](=[O:45])[C:43]([CH3:46])=[CH:42][C:41]3=[O:47])[CH:39]=2)[NH3+:36])[C:28](=[O:29])[CH:27]=1>N1C=CC=CC=1>[S:1]([NH:36][C:35]1[CH:37]=[C:38]([N:40]2[C:44](=[O:45])[C:43]([CH3:46])=[CH:42][C:41]2=[O:47])[CH:39]=[C:33]([N:30]2[C:31](=[O:32])[C:26]([CH3:25])=[CH:27][C:28]2=[O:29])[CH:34]=1)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CC1=CC(=O)N(c2cc([NH3+])cc(N3C(=O)C=C(C)C3=O)c2)C1=O
Agent: O=C([O-])C(F)(F)F
Solvent: c1ccncc1
Product: CC1=CC(=O)N(c2cc(NS(=O)(=O)c3cccc4c(N(C)C)cccc34)cc(N3C(=O)C=C(C)C3=O)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.3 %

Procedure:
Dansyl chloride (139 mg, 0.517 mmol) in pyridine (3 mL) was added to a pyridine solution of 4 (200 mg, 0.517 mmol). The resulting mixture was stirred at 25° C. for 18 hours after which the volatiles were evaporated under reduced pressure. The resulting oil was taken back in CHCl3 and the organic phase was washed with aqueous saturated Na2CO3, dried over MgSO4 and evaporated. The crude was purified by flash chromatography on silica gel (Tol/EtOAc 10%) giving 5 as a light green solid (40 mg, 0.074 mmol, 16%). 1H NMR (400 MHz, (CD3)2CO) δ 9.71 (s, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.39 (dd, J1=1.2, 7.2 Hz, 1H), 7.62-7.58 (td, J=1.2, 7.2 Hz, 2H), 7.28-7.27 (m, 3H), 7.11 (t, J=2.0 Hz, 1H), 6.63-6.61 (m, 2H); 13C NMR (75 MHz, (CD3)2CO) δ 171.3, 170.4, 152.8, 135.4, 134.0, 131.7, 131.5, 130.3, 130.2, 129.6, 128.7, 124.9, 119.8, 119.6, 116.6, 115.9, 46.3, 12.1; HRMS (ESI) Calculated for C28H25N4O6S [M+H]+: 545.1516. Found: 545.1489. m.p.: 230° C.
Reaction SMILES: [CH2:1]([C:4]1([CH2:20]C=C)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]>ClCCl.CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=C1CC(Cl)(Cl)CCC1P(=CC1C=CC=CC=1)(C1CCCCC1)C1CCCCC1.[Ru]>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C:4]3([CH2:1][CH:2]=[CH:3][CH2:20]3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CCC1(CC=C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [Ru]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=C2CC(Cl)(Cl)CCC2P(=Cc2ccccc2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CC=CC2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)-dichloro-(phenylmethylene)-(tricyclohexylphosphine)-ruthenium (Grubbs' 2nd generation metathesis catalyst, 1.00 g) is added to a solution of (S)-6,6-diallyl-3-[1-(4-bromo-phenyl)-ethyl]-[1,3]oxazinan-2-one (8.65 g) in dichloromethane (120 mL) at room temperature. The resulting solution is stirred at room temperature overnight and then concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 3:2→0:1) to afford the title compound as a greyish solid. Yield: 6.11 g (77% of theory); LC (method 1): tR=3.68 min; Mass spectrum (ESI+): m/z=336/338 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.OS(O)(=O)=O>CC(O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1c2c(nc3ccccc13)CCC=C2
Temperature: 0 °C
Yield: 51 %

Procedure:
In 50 ml of HOAc was dissolved 3.00 g of 9-amino-1,2,3,4-tetrahydroacridin-1-ol. To this mechanically stirred solution at room temperature was added 0.75 ml (1 eq) of H2SO4. The reaction mixture was warmed on a steam bath causing a precipitate to form. After 0.5 hour of heating, the reaction was complete based on thin layer chromatography. The reaction mixture was poured into excess ice/10% NaOH and the precipitate was collected. The precipitate was dissolved in dichloromethane, dried over MgSO4, filtered, and evaporated to a solid which was purified by silica gel chromatography to yield a solid. Two recrystallizations from dichloromethane/hexanes yielded 1.40 g (52%) of a powder, melting point 178°-179° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[O:27]=[C:11]1[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and pyridine-2-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.932 min, m/z=430.1; 1H NMR (CDCl3) 1.52 (d, 3H), 1.90 (m, 1H), 2.13 (m, 1H), 2.21 (m, 4H), 2.45 (m, 1H), 2.82 (m, 1H), 5.15 (s, 1H), 5.35 (s, 1H), 5.65 (m, 1H), 6.98 (d, 2H), 7.13-7.32 (m, 6H), 7.56 (m, 1H), 7.65 (m, 3H), 8.57 (d, 1H).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(#N)C>[NH:20]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]1
Reactant: CS(=O)(=O)Nc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)Nc1cccc(OCc2c[nH]cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(1-trityl-1H-imidazol-4-ylmethoxy)-phenyl]methanesulfonamide (0.63 g, from above) and 1N HCl (10 mL) in acetonitrile (10 mL) was stirred at room temperature overnight. The solvent was removed and the residue was brought to basic pH with saturated potassium carbonate solution. The mixture was extracted with dichloromethane, washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel eluting with methanol (containing 2% NH4OH)/dichloromethane (7:93) to give N-[3-(1H-imidazol-4-ylmethoxy)-phenyl]methanesulfonamide. This was converted to N-[3-(1H-imidazol-4-ylmethoxy)-phenyl]methanesulfonamide oxalate salt, mp 178-180° C. by treating with 1M oxalic acid in ether.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=O)=[CH:8][C:7]=1[C:16]1[N:17]=[N:18][C:19]([N:22]([CH3:33])[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[CH:20][CH:21]=1.[NH2:34][C:35]([NH2:37])=[S:36].II>CO>[CH3:4][O:5][C:6]1[C:7]([C:16]2[N:17]=[N:18][C:19]([N:22]([CH3:33])[CH:23]3[CH2:24][C:25]([CH3:32])([CH3:31])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]3)=[CH:20][CH:21]=2)=[CH:8][C:9]2[CH2:10][C:11]3[S:36][C:35]([NH2:37])=[N:34][C:12]=3[C:13]=2[CH:14]=1
Reactant: NC(N)=S
Reactant: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)CCC2=O
Agent: II
Solvent: CO
Solvent: CCO
Product: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)Cc1sc(N)nc1-2
Temperature: 100 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a microwave vial containing ethanol (1.2 mL) was added 6-methoxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one (Intermediate 7-1, 100 mg, 0.25 mmol), thiourea (55.9 mL, 0.73 mmol), and iodine (124 mg, 0.49 mmol). The reaction mixture was stirred at 100° C. for 3 hours. The mixture was diluted with MeOH and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford 5-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H-indeno[1,2-d]thiazol-2-amine (114 mg) MS [M+H+]=465.0.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=2[O:21]C)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.N1C=CC=CC=1.O>CCOCC>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[OH:21])[CH3:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC)c(C(C)COCCc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CC(COCCc1ccccc1)c1cc(O)ccc1O
Temperature: 190 °C

Procedure:
A mixture of 2-(2,5-dimethoxyphenyl)propyl 2-phenylethyl ether (195 mg., 0.65 mM), pyridine (0.4 ml., 4.96 mM) and dry pyridine hydrochloride (4 g., 34.6 mM) is heated at 190° C. for 6 hours. The reaction mixture is cooled and added to a mixture of water (100 ml.) and ether (150 ml.). The ether extract is washed once with water (50 ml.) and, along with a second ether extract (50 ml.) of the aqueous phase, is dried over magnesium sulfate and evaporated to dryness. The residue is purified via preparative layer chromatography on silica gel plates by elution with ether-pentane.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>O1CCCC1.[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh]>[S:20](=[O:22])(=[O:21])([OH:24])[OH:23].[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1=CNCCN1C(=O)C(F)(F)F
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: F[B-](F)(F)F
Solvent: C1=CCCC=CCC1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1CNCCN1C(=O)C(F)(F)F
Reaction time: 18 h
Yield: 100730.1 %

Procedure:
2.50 g (8.95 μmol) of 1-trifluoroacetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide, 7.5 mg (18 μmol) of bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate and 11.5 mg (21 μmol) of 1-[1(R)-(di-tert-butylphosphino)ethyl]-2-(S)-(diphenylphosphino)ferrocene were placed in a 50 ml autoclave under argon (educt:catalyst=486). A solution of 0.89 g (9.08 mmol) of sulfuric acid in 20 ml of degassed tetrahydrofuran was then added. Hydrogenation was then carried out for 18 hours at 200° C. under a hydrogen pressure of 13-10 bar. After distillation of the solvent, 3.42 g (>99%) of the title compound were obtained in the form of a white powder. After cleavage of the protecting groups, the enantioselectivity of the hydrogenation was determined by GC analysis, giving an ee of 79.5 percent. Other data concerning the title compound was:
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S-:9][C:10]#[N:11].[NH4+].Cl>C(O)C>[N:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:9][C:10]=1[NH2:11]
Reactant: Nc1cccnc1Cl
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: Nc1nc2cccnc2s1
Temperature: 85 °C
Yield: 43.1 %

Procedure:
A suspension of 2-chloro-3-aminopyridine (3 g, 23 mmole), and ammonium thiocyanate (3.5 g, 46.5 mmole) in 23 mL of ethanol was acidified with conc. HCl to pH ˜1 (˜1.8 mL). The reaction mixture was heated to 85° C. for 3 days. At this point, the solvent was evaporated and residual water was removed aziotropically by the distillation of 2-propanol. The yellow residue was mixed with 12 mL of 7 M ammonium hydroxide and 7 mL of chloroform. The solid was isolated by filtration to yield 1.50 g (43%) of the product as a white powder. MS (m/z, ES+): 152 (M+1, 100%).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1CCCCC1)C.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[C:18]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=C1CCCCCN1
Solvent: CN(C)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)N1CCCCCC1=O
Temperature: 67.5 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
113 g (1 mol) of ε-caprolactam (purity >99% by weight) are dissolved in 200 ml of toluene in a round-bottom flask. 127 g (1 mol) of N,N-dimethylcyclohexylamine are introduced into this. Then, at 40-70° C., 164.2 g (1 mol) of octanoyl chloride (purity 99% by weight) are added dropwise. The reaction mixture is then stirred at 65-70° C. for one hour. Then, to remove the ammonium salt produced, it is washed first once with 130 ml of hot water and then with 10 ml of concentrated HCl dissolved in 130 ml of hot water. It is subsequently washed 3 more times with 130 ml of hot water in order to maintain a pH of 5-7 in the reaction mixture. The solvent is distilled off under reduced pressure (water pump) at 70-80° C. N-octanoylcaprolactam is obtained as a yellow liquid in 93% yield with a purity of 98%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][N:49]=1.[C:55]([O:59][C:60](=[O:80])[CH2:61][CH:62]1[CH2:67][CH2:66][N:65]([C:68]2[S:69][C:70]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75](Br)[N:74]=3)=[CH:71][N:72]=2)[CH2:64][CH2:63]1)([CH3:58])([CH3:57])[CH3:56].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:55]([O:59][C:60](=[O:80])[CH2:61][CH:62]1[CH2:63][CH2:64][N:65]([C:68]2[S:69][C:70]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([NH:47][C:48]4[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][N:49]=4)[N:74]=3)=[CH:71][N:72]=2)[CH2:66][CH2:67]1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)CC1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1
Reactant: Cc1ccnc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(CC(=O)OC(C)(C)C)CC4)s3)n2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.85 g, 2.97 mmol) and palladium acetate (500 mg, 2.22 mmol) were suspended in toluene (30 ml), and after 2-amino-4-picoline (1.60 g, 14.8 mmol) and {1-[5-(6-bromopyridin-2-yl)-thiazol-2-yl]piperidin-4-yl}acetic acid tert-butyl ester (6.50 g, 14.8 mmol) obtained in Step 2 were sequentially added, cesium carbonate (7.25 g, 22.2 mmol) was added, and the mixture was stirred overnight at 100° C. Water was added to the reaction solution and extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over anhydrous sodium sulfate and the residue obtained by vacuum concentration was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:1 to 1:10) and the title compound (4.30 g, 62%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>[Cu]I.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.C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(N2CCC(C)(C)c3ccc(Br)cc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2CCC(C)(C)c3ccc(C#C[Si](C)(C)C)cc32)cc1
Temperature: 75 °C

Procedure:
To a solution of 0.20 g (0.6 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)-7-bromoquinoline (Compound 1) in 2.90 g (4.0 mL, 29 mmol) of triethylamine were added 0.030 g (0.16 mmol) of copper(I) iodide, 0.35 g (0.50 mL, 3.5 mmol) of (trimethylsilyl)acetylene and 0.074 g (0.11 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting mixture was heated at 75° C. for 20 hours. The reaction mixture was cooled, methylene chloride was added and the mixture was adsorbed onto silica gel. The mixture was separated by flash chromatography (hexanes) to give the title compound as a yellow solid. PNMR (300 MHz, CDCl,) d 0.20 (9 H, s), 1.35 (6 H, s), 1.84 (2 H, t, J=6.0 Hz), 2.39 (3 H, s), 3.59 (2 H, t, J=6.0 Hz), 6.78 (1 H, d, J=1.7 Hz), 6.84 (1 H, rid, J=7.8,1.7 Hz), 7.12-7.17 (5 H, several overlapping d's).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:11]([I:12])[C:4]=2[O:3]1.[BH4-].[Na+]>CO>[O:17]=[S:2]1(=[O:1])[NH:7][CH2:6][C:5]2[CH:8]=[C:9]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:10]=[C:11]([I:12])[C:4]=2[O:3]1
Reactant: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(I)c2c(c1)CNS(=O)(=O)O2
Temperature: 20 °C

Procedure:
To a solution of 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine (2 g., 5.5 millimole) in methanol (75 ml.) is added sodium borohydride (0.21 g., 5.5 millimole) portionwise with stirring at 20° C. The resulting reaction solution is stirred at 20° C. for 16 hours and then concentrated in vacuo leaving a residual solid which is triturated with water (50 ml.). The insoluble solid is collected and crystallized from 40% ethanol-acetic acid (25:2; v:v) to give 2,2-dioxo-3,4-dihydro-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine as colorless crystals (1.7 g., 85%), m.p. 154°-155° C.
Reaction SMILES: C1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(CN)CCCCC1>C(O)(=O)C>[CH:29]1([CH2:28][N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NCC1CCCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1CC1CCCCC1
Yield: 73.3 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclohexanemethylamine (0.129 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 102.3 mg (0.32 mmol, 73.3% yield) of the title compound.
Reaction SMILES: NN.[N:3]1([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]4[C:22]([C:26]5[CH:31]=[C:30]([F:32])[N:29]=[CH:28][C:27]=5[O:33][CH2:34][CH2:35][N:36]5C(=O)C6C(=CC=CC=6)C5=O)=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[C:14]([F:47])=[CH:13][N:12]=2)[CH:7]=[CH:6][N:5]=[N:4]1>C(O)C>[N:3]1([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]4[C:22]([C:26]5[C:27]([O:33][CH2:34][CH2:35][NH2:36])=[CH:28][N:29]=[C:30]([F:32])[CH:31]=5)=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[C:14]([F:47])=[CH:13][N:12]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Agent: NN
Solvent: CCO
Product: NCCOc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
Add hydrazine (0.03 mL, 0.8 mmol) to a solution of 2-(2-(4-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-6-fluoropyridin-3-yloxy)ethyl)isoindoline-1,3-dione (0.25 g, 0.4 mmol) in ethanol (5 mL). Stir the mixture at 40° C. overnight. Remove the solvent and purify the residue by column chromatography (10% methanol in DCM) to afford the title compound (70 mg, 35%). MS (ES) m/z 495 [M+1]+.
Reaction SMILES: [C:1]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:19].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:17])=[O:18]
Reactant: O=C1CCCCCCCCCCCCCCCO1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCCCCCCCCCO
Reaction time: 8 h
Yield: 97 %

Procedure:
A 5 liter three neck round bottom flask, equipped with a mechanical stirrer and reflux condenser, was charged with 300 g (1.16 moles) of 99% hexadecanolide, 1000 mls of 50% sodium hydroxide, 1500 mls of toluene and 5.6 g (0.01 6 moles) of 97% tetrabutylammonium hydrogen sulfate. The reaction mixture stirred at 85°-95° C. overnight, the reaction was cooled, and filtered under vacuum. The filtered solid was washed with diethyl ether before being added to water and acidified to pH=1.5 with concentrated hydrochloric acid. The precipitated product was filtered under vacuum, washed several times with water and dried at 50°-60° C. under high vacuum to give 353 g (1.2 moles) of 97% 16-hydroxy hexadecanoic acid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CCOC(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccnc1Nc1ccccn1
Temperature: 20 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
A mixture of (3-nitro-pyridin-2-yl)-pyridin-2-yl-amine (0.84 g, 3.89 mmol) and 10% palladium on carbon (0.30 g) in EtOAc (20 mL) was stirred under an atmosphere of hydrogen at atmospheric pressure and 20° C. for 16 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound as a green solid (0.63 g, 88%). LCMS (method H): Rt 1.87 min, [M+H]+ 187.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2)C.[OH-].[K+]>O.C(O)C>[C:7]12([O:6][CH2:5][C:4]([OH:17])=[O:3])[CH2:16][CH:11]3[CH2:10][CH:9]([CH2:15][CH:13]([CH2:12]3)[CH2:14]1)[CH2:8]2
Reactant: CCOC(=O)COC12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COC12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of (adamantan-1-yloxy)-acetic acid ethyl ester (A. F. Noels et al. Tetrahedron, 1982, 38, 2733) (7.29 g, 29 mmol) and potassium hydroxide (2.60 g, 46 mmol) in water-ethanol (1:2 mixture, 180 ml) was heated at reflux for 2 h. The mixture was cooled, then concentrated in vacuum and acidified with concentrated hydrochloric acid. The resultant white precipitate was dissolved in ethyl acetate (200 ml). The solution was washed with brine (2×200 ml), dried (MgSO4) and the solvent was evaporated to afford white crystalline solid (5.85 g 92%). 1H NMR (300 MHz, CDCl3) 4.08 (2H, s), 2.20-1.58 (15H, m).