Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:8][C@@H:6]([OH:7])[C@H:5]([OH:9])[C@H:4]([OH:10])[C@H:3]1[O:11][CH3:12].[CH3:14][CH:15]([CH3:41])[CH2:16][O:17][C:18]([C:20]1[C:21](=[O:40])[O:22][C:23]2[C:37]([CH3:38])=[C:36](O)[CH:35]=[CH:34][C:24]=2[C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19]>C(OCC)C.CCCCCC>[CH3:14][CH:15]([CH3:41])[CH2:16][O:17][C:18]([C:20]1[C:21](=[O:40])[O:22][C:23]2[C:37]([CH3:38])=[C:36]([O:7][C@@H:6]3[O:8][C:2]([CH3:13])([CH3:1])[C@H:3]([O:11][CH3:12])[C@@H:4]([OH:10])[C@H:5]3[OH:9])[CH:35]=[CH:34][C:24]=2[C:25]=1[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:19]
Reactant: Cc1c(O)ccc2c(OCc3ccccc3)c(C(=O)OCC(C)C)c(=O)oc12
Reactant: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)OC1(C)C
Solvent: CCOCC
Solvent: CCCCCC
Product: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](Oc2ccc3c(OCc4ccccc4)c(C(=O)OCC(C)C)c(=O)oc3c2C)OC1(C)C

Procedure:
The operation is carried out as in Example 1 Stage A, starting from 6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranose and 2-methylpropyl-7-hydroxy-8-methyl-2-oxo-4-(phenylmethoxy)-2H-1-benzopyran-3-carboxylate, the sought product is obtained. rf=0.22 hexane-ethyl acetate (1-2).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]1[C:17]2[C:24]([CH3:25])=[C:23]([C:26]([NH2:28])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(N(CC)C(C)C)(C)C.C(Cl)Cl.[C:41](Cl)(=[O:43])[CH3:42]>O>[C:41]([NH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]1[C:17]2[C:24]([CH3:25])=[C:23]([C:26]([NH2:28])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1)(=[O:43])[CH3:42]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@@H]3N)c12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)N[C@H]1CCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(N)=O)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.15 g (1S,2S) 4-[2-(2-amino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl thieno[2,3-d]pyrimidine-6-carboxylic acid amide and 0.32 ml N,N-diisopropylethylamine were mixed with DCM. 0.027 g acetylchloride were added to the mixture and stirred for 1 hour at rt. Then the reaction mixture was diluted with water and filtrated. The solid was air-dried.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([NH:13][C:14]1[NH:22][C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]=2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([NH:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=2[NH2:25]
Reactant: ClCCCCBr
Reactant: CCC[C@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from N2-[(1S)-1-methylbutyl]-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNCCOC.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([O:77]CC3C=CC=CC=3)=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH2:70][O:71][CH3:72])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1>CO.ClCCl>[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([OH:77])=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH2:70][O:71][CH3:72])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1
Reactant: COCCN1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: COCCNCC[C@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COCCN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 60 %

Procedure:
In a manner similar to that described in example Z-35, from 16 (15 mg, 0.034 mmol) and [(3S)-3-Aminobutyl][2-(methyloxy)ethyl]amine bis hydrochloride (19 mg, 0.087 mmol), (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid after silica gel chromatography (1-12% methanol/dichloromethane). This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a yellow solid (9 mg, 60%, 2 steps). 1H NMR (CDCl3) δ 12.56 (s, 1H), 10.51 (m, 1H), 8.29 (s, 1H), 7.32 (m, 2H), 6.98 (m, 2H), 5.03 (m, 1H), 4.65-4.59 (m, 2H), 4.53 (m, 1H), 4.21 (m, 1H), 3.61-3.40 (m, 2H), 3.34-3.13 (m, 3H), 3.08 (m, 1H), 2.94-2.84 (m, 2H), 2.68 (m, 1H), 2.07 (m, 1H), 1.50 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.14 (m, 1H); ES+ MS: 459 (M+1).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[C:6]1([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:18]1([C:13]2[C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:23]=[CH:22][C:21]([S:1]([OH:5])(=[O:4])=[O:3])([S:1]([OH:3])(=[O:5])=[O:4])[CH2:20][CH:19]=1
Reactant: c1ccc(-c2ccccc2-c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)C1(S(=O)(=O)O)C=CC(c2ccccc2-c2ccccc2)=CC1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
880 g of concentrated sulfuric acid were heated to 110° C, and 270.5 g of terphenyl were added. The temperature was raised to 140° C and left on that level for 4 hours. After cooling down to 100° C, 800 ml of water were added dropwise, and the mixture was allowed to cool and then filtered with suction, giving a crude product which was used direct in the next stage. Purity (HPLC): 99.7%; yield: 565 g.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].[C:12]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]>C1CCCCC1>[C:12]([N:16]([CH2:8][CH2:9][CH2:10][Cl:11])[C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NC(C)(C)C
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Product: CC(C)(C)N(CCCCl)C(C)(C)C
Reaction time: 20 h
Yield: 50.8 %

Procedure:
To a stirred suspension of K2CO3 (200 g, 1.5 mole) in cyclohexane 200 mL and 1-bromo-3-chloropropane (540 gms, 3.4 mole) is added dropwise over a period of 1 h at 20C di-t-butyl amine (289 g, 2.24 mole). After complete addition the reaction is allowed to stir for an additional 20 h. The crude reaction mixture is filtered and then washed with saturated NaCl (3×100 mL). The organic phase is extracted with 3N HCl (3×100 mL). The resulting aqueous phase, containing the desired product as the hydrochloric salt, is washed with hexanes (3×100 mL) to remove any residual BCP. The aqueous phase is subsequently basified with 50 wt % NaOH and extracted with cyclohexane (3×100 mL). After solvent removal 234 g (51% yield) of the title compound is isolated as a yellow oil.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]1([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#N)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C([O:26]CC)C.S(=O)(=O)(O)O>C(Cl)Cl>[C:10]1([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[O:26])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: CCOCC
Reactant: N#Cc1ccccc1C1=CCCCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=Cc1ccccc1C1=CCCCC1

Procedure:
360 ml. (0.36 mol) 1M DIBAH solution in methylene chloride was added dropwise in the course of 1.5 hours, while cooling to -15° to -10° C., into a solution of 60.5 g. (0.33 mol) o-(1-cyclohexenyl)-benzonitrile in 500 ml. anhydrous diethyl ether, stirred for a further hour at 0° C., subsequently for 3 hours at ambient temperature and decomposed with 5N sulphuric acid. The precipitate obtained was filtered off with suction and the organic phase was washed with an aqueous solution of sodium chloride, dried and evaporated. The aldehyde obtained was used for the following stage without further purification (crude yield 95% of theory). NMR,(60 MHz, CDCl3, ppm): 10.25 (1H, s, --CHO); 6.90-8.10 (4H, m. aromat. protons); 5.70 (1H, m, olef. proton); 1.05-2.50 (8H, m, cyclohexenyl radical).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH3:6])[CH3:3].[CH2:7]([O:14][NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][N:15]([CH:2]([CH3:3])[CH2:4][CH2:5][CH3:6])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCC(C)Br
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Product: CCCC(C)N(OCc1ccccc1)C(=O)Nc1ccccc1
Yield: 67.8 %

Procedure:
Using the general method of Compound 42 Part B, 2-bromopentane (2.7 mL, 21.7 mmole) was reacted with 1-benzyloxy-3-phenylurea (4.9 g, 20.1 mmole) to provide 4.26 g of 1-benzyloxy-1-(1-methylbutyl)-3-phenylurea as a yellow oil.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.Br[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:26][C:21]1[CH:20]=[CH:19][CH:25]=[C:24]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH3:7])[C:22]=1[NH2:23]
Reactant: CSc1ccccc1B(O)O
Reactant: Nc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CSc1ccccc1-c1cccc(F)c1N
Yield: 80.4 %

Procedure:
A benzene solution (100 mL) of 2-methylthiophenylboronic acid (2.07 g, 12.3 mmol); 4-bromo-2-fluoro aniline (1.06 g, 5.6 mmol); aq. Na2CO3 (12.5 mL, 2 M, 25 mmol); and tetra n-butyl ammonium bromide (90 mg, 0.3 mmol) was purged with vacuum and Ar. Bis(triphenylphosphine)palladium (II) chloride (195 mg, 0.3 mmol) was added, and the reaction was refluxed 10 h. After cooling, the reaction was diluted with EtOAc and H2O, the layers were separated, the organic was dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (10% EtOAc/hexanes) to yield the desired product (1.05 g, 81%). 1H NMR (CDCl3) δ: 7.29 (m, 2H); 7.18 (m, 2H); 7.09 (dd, 1H, J=11.7, J′=1.8); 7.01 (dd, 1H, J=8.0, J′=1.4); 6.82 (t, 1H, J=9.2); 3.79 (bs, 2H); 2.38 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]C)=O)[NH:6]2.CC(C)([O-])C.[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].Cl>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:12](=[O:14])[CH:23]([C:22]([O:26][CH3:27])=[O:25])[CH2:24][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1Cn2c(cc3c(Br)cc(F)cc32)C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 81.8 %

Procedure:
To a suspension of the indole of Step 4 (4 g, 15 mmol) in a mixture of 10:1 toluene/THF (100 mL) at r.t. was added potassium t-butoxide (15 mL of a 1M solution in THF). The reaction mixture was stirred for 2 minutes and methyl acrylate (2.5 g, 30 mmol) was added. The mixture was stirred at reflux for 5 hours and cooled to r.t. Then 1N HCl was added to acidify to pH 3 and the reaction mixture was extracted with EtOAc and the combined organic layers were concentrated. The residue was swished in EtOAc/Hexanes to give 4 g of the desired compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH:17]=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH2:17][NH:23][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: Cn1c(=O)c(C=O)c(N)n(-c2ccccc2)c1=O
Product: CCCCNCc1c(N)n(-c2ccccc2)c(=O)n(C)c1=O

Procedure:
Reductive amination of 6-amino-5-formyl-3-methyl-1-phenyl-2,4 (1H, 3H) -pyrimidinedione with N-butylamine was performed in substantially the same manner as Example 18 to thereby give an intermediate, 6-amino-5-(N-butylaminomethyl)-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione. The intermediate was reacted with 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid by a conventional condensation method to give the title compound (yield 36%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:17][NH:18][CH3:19].[BH3-]C#N.[Na+].Cl>CO>[CH3:17][N:18]([CH3:19])[CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-oxo-piperidin-1-yl)-benzonitrile (100 mg, 0.5 mmol, reference example 116) dimethylamine hydrochloride (408 mg, 5 mmol) and NaCNBH3 (25 mg, 0.4 mmol) was dissolved in MeOH (7 mL) and stirred at room temperature overnight. After 24 h, additional NaCNBH3 (24 mg, 0.38 mmol) was added and the mixture was stirred overnight at room temperature. The pH of the mixture was adjusted to pH 2 with concentrated HCl and extracted with Et2O (3×). The aqueous phase was adjusted to pH 10 with KOH pellets, and extracted (3×) with Et2O. The latter combined organic phases were washed with brine, dried with Na2SO4, filtered and evaporated. The crude material was taken into the next step without further purification. 1H NMR (CDCl3): δ 7.44 (d, 2H), 6.83 (d, 2H), 3.86 (m, 2H), 2.86 (dt, 2H), 2.32-2.38 (m, 1H), 2.28 (s, 6H), 1.92 m(m, 2H), 1.54 (dq, 2H). MS (EI) m/z 229 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: Clc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(N2CCc3ccccc32)n1
Yield: 49.6 %

Procedure:
A solution of 2,4-dichloropyrimidine (596 mg, 4.0 mmol), indoline (0.45 ml, 4.0 mmol) and N,N-diisopropylethylamine (0.69 ml, 4.0 mmol) in n-butanol (20 ml) was heated at 100° C. for 18 hours. Silica (3 g) was added and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 0-40% ethyl acetate/isohexane, to give the product as a colourless solid (460 mg, 50%). NMR (CDCl3): 3.2 (t, 2H), 4.0-4.1 (t, 2H), 6.5 (d, 1H), 7.0-7.1 (m, 1H) 7.2-7.3 (m, 2H), 8.2 (m, 1H), 8.3-8.4 (m, 1H); MS (MH+): 232.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[Sn]Cl.O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1Nc1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc(Br)c1Nc1ccccc1
Yield: 73.8 %

Procedure:
(2-Bromo-6-nitrophenyl)phenylamine (6.5 g, 22.7 mmol) was dissolved in EtOAc (100 mL) and SnCl2.H2O (25 g) added under a nitrogen atmosphere. The resulting mixture was heated at reflux for 5 h. The cooled reaction mixture was diluted with NaHCO3 (aq. satd. solution, 100 mL) and additional NaHCO3 added until all effervescence had ceased. The mixture was filtered through Celite® to remove insoluble inorganic material. The EtOAc layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (Si—PCC, 0-50% EtOAc in cyclohexane) to give the product as a yellow crystalline solid (4.41 g, 77%). 1H NMR (300 MHz, CDCl3): δ 7.24-7.17 (2H, m), 7.01 (1H, dd, J=8.0, 1.5 Hz), 6.94 (1H, d, J=7.9 Hz), 6.85 (1H, dt, J=7.4, 1.0 Hz), 6.72 (1H, dd, J=7.9, 1.5 Hz), 6.67-6.61 (2H, m), 5.36 (1H, br s), 3.97 (2H, br s)
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(C)C)(=O)C.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH2:35][CH2:36][C:37](=O)[C:38]#[C:39][Si](C)(C)C)[C:31]([O:33]C)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].FC(F)(F)C(O)=O>>[C:22]([O:26][C:27]([N:29]1[C@@H:37]([C:38]#[C:39][CH3:1])[CH2:36][CH2:35][C@H:30]1[C:31]([OH:33])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H](CCC(=O)C#C[Si](C)(C)C)NC(=O)OC(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Temperature: -10 °C

Procedure:
A 2-L, 3-neck jacketed round-bottomed flask equipped with an overhead mechanical stirrer, N2-inlet, temperature probe and addition funnel was charged with sodium triacetoxyborohydride (93.0 g, 0.44 mol), isopropyl acetate (100 g) and an isopropyl acetate solution obtained from Example 1 (27.8 wt %, 410 g, 0.33 mol). The resulting mixture was chilled to −10° C. (internal temperature). Trifluoroacetic acid (170 g, 1.5 mol) was added dropwise by addition funnel over a 2-hour period. The internal temperature was adjusted to 10° C. and the mixture was stirred until HPLC analysis indicated complete consumption of starting material (about 15 hours). The reaction was poured into 750 g of 25% K2HPO4 (prepared by dissolving 250 g of K2HPO4 in 750 g of water). The pH of the mixture was adjusted to 6.6 using 20% KOH (prepared by dissolving 100 g of KOH in 400 g of water). The layers were separated. The organic layer was washed with 25% K2HPO4 (250 g) and with water (250 g). The organic layer was distilled to remove isopropyl acetate, which was chased with ethanol to a final volume of about 250 mL. The solution was cooled to 0° C. and 3.5 M LiOH solution (prepared by dissolving 37 g of LiOH—H2O in 250 g of water) was added such that the temperature remained below 20° C. The reaction progress was followed by HPLC until no ester remained (typically about 2 hours). The ethanol was removed by distillation under vacuum and the resulting aqueous layer was extracted with methyl tert-butyl ether (190 g). The methyl tert-butyl ether layer was extracted with water (100 g) and discarded. The combined aqueous layers was cooled to 0° C. and neutralized to pH 7 with concentrated HCl. Isopropyl acetate (220 g) was added and the pH was adjusted to 3 with concentrated HCl. The layers were separated and the aqueous layer was extracted with isopropyl acetate (220 g). The combined organic layers were washed with water (100 g). The organic solution was distilled under vacuum to a total volume of about 180 mL, and cooled to 0° C. Crystals formed over a 30-minute period. Heptanes (50 g) was added dropwise over a 2-hour period and the resulting mixture was stirred for 2 hours at 0° C. The mixture was filtered and the solid was washed with cold 1:1 isopropyl acetate/heptanes (50 mL) and dried under vacuum to afford the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.24 (s, 9H) 1.45 (s, 9H) 1.87-2.04 (m, 1H) 2.11-2.28 (m, 1H) 2.57-2.81 (m, 2H) 3.75 (s, 3H) 4.23-4.40 (m, 1H) 4.99-5.14 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[CH2:13][CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[CH2:13][CH2:12][CH2:11][N:10]([C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(Cl)c2)CCCN(Cc2ccccc2)C1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCCC(O)(c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a stirred solution of 13 parts of 3-(3-chlorophenyl)-1-(phenylmethyl)-3-piperidinol in 270 parts of methylbenzene were added dropwise 10.9 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued overnight at reflux temperature. After cooling to room temperature, the whole was washed with water and hydrochloric acid. The organic layer was dried, filtered and evaporated, yielding 7 parts (58%) of ethyl 3-(3-chlorophenyl)-3-hydroxy-1-piperidinecarboxylate as a residue (intermediate 50).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][S:9][CH:10]=1)CCC.Cl[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>>[N+:25]([C:24]1[CH:23]=[CH:22][S:21][C:20]=1[C:6]1[N:7]=[CH:8][S:9][CH:10]=1)([O-:27])=[O:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: O=[N+]([O-])c1ccsc1-c1cscn1

Procedure:
4-(3-Nitrothiophen-2-yl)thiazole was prepared from 4-(tributylstannyl)thiazole (0.51 g, 1.31 mmol) and 2-chloro-3-nitrothiophene (0.21 g, 1.31 mmol) according to protocol E. Retention time (min)=2.012, method [1], MS (ESI) 212.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>CN(C)P(N(C)C)(N(C)C)=O>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: OCCCCCCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: N#Cc1ccc(NCCCCCCCCCCCCCCCCO)cc1
Temperature: 120 °C

Procedure:
p-Aminobenzonitrile (12 g.) and 16-bromo-1-hexadecanol (15 g.) are dissolved in hexamethylphosphoramide (200 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water (50 ml.) is added gradually. The mixture is then chilled in an ice-bath. The precipitate separated is filtered, washed thoroughly with water, and dried. It is then washed repeatedly with hexane and dried. The pale brownish yellow granular solid is obtained as a homogeneous product. Recrystallization from ether-hexane affords 4-(16-hydroxyhexadecylamino)benzonitrile as pale yellow prisms.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:33])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: O=C(Cl)c1cccnc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2cccnc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-4-oxo-1-phenyl-3-{[(pyridine-3-carbonyl)-amino]-methyl}-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and nicotinoyl chloride. MS calcd. for C24H19ClN3O4 [(M+H)+] 448.1, obsd. 447.9.
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([I:38])=[C:34]([CH:37]=1)[CH2:35]O>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([I:38])=[C:34]([CH:37]=1)[CH2:35][N:15]=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Cl)ccc1I
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cc(Cl)ccc1I
Temperature: 25 °C
Yield: 107.7 %

Procedure:
DPPA (0.442 mL, 2.05 mmol) followed by DBU (0.306 mL, 2.05 mmol) were added to a stirred solution of 5-chloro-2-iodobenzyl alcohol (500 mg, 1.86 mmol) in DMF (10 mL) at 0° C. and the reaction mixture was warmed to room temperature. After 16 h the mixture was warmed to 70° C. for 2 hr. The reaction was then concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated to give 5-chloro-2-iodobenzylazide (588 mg): 1H NMR (CDCl3, 400 MHz) δ 4.43 (s, 2H), 7.03 (dd, J=2.6, 8.4 Hz, 1H), 7.39 (d, J=2.6, 1H), 7.78 (d, J=8.4 Hz, 1H).