Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][CH2:7][CH:8]([OH:34])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.I[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([O:34][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:35][CH:36]=1
Reactant: CCCCCI
Reactant: OC(COc1ccc(Br)cc1)COc1ccc(C(CCCc2ccccc2)OC2CCCCO2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCOC(COc1ccc(Br)cc1)COc1ccc(C(CCCc2ccccc2)OC2CCCCO2)cc1

Procedure:
A mixture of the product (0.57 g) of Step 3, 0.3 mL of 1-iodopentane and 80 mg of Nail in 20 ml of 1:1 THF/DMF was refluxed for 4 hrs. The mixture was then quenched with 5 mL of MeOH, 20 mL of Sat. NH4Cl, and extracted with 50 mL of Et2O. The extract was dried over NaSO4 and concentrated. The residue was purified by flash chromatography eluted with EtOAc and hexanes (7:1) to give 0.6 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[CH:18]1([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=3)[CH2:24][CH2:23]2)[C:14]([C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[F:17])[O:13][N:12]=2)=[O:16])[CH2:19][CH2:20]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)no2)c(F)c1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3cc(-c4ccc(C#N)cc4F)on3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid and cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine following a procedure analogous to that described in Example 18. LC (method 18): tR=1.23 min; Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C:24]=3[N:25]2[CH3:28])=[CH:21][CH:20]=1>>[CH3:28][N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=4)=[CH:10][C:11]3=[O:15])[CH:27]=2)[C:23]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C:24]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 57.9 %

Procedure:
4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (86 mg, 0.36 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (120 mg, 0.32 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (97 mg, 58%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 4H), 7.58-7.52 (m, 2H), 7.36 (s, 1H), 7.08 (dd, J=8.2, 1.8 Hz, 1H), 6.92 (d, J=1.9 Hz, 1H), 6.50 (dd, J=7.2, 2.0 Hz, 1H), 4.65 (br m, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.81 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.CC(C)([O-])C.[K+].C([O:31][N+:32]([O-])=[O:33])(C)C>CC(C)=O.CCCCCC>[OH:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[C:15]([N+:32]([O-:33])=[O:31])[C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
By the method of example 1, testosterone (2.88 g, 10 mM), potassium tert-butoxide (3.40 g, 30 mM) and iso-propylnitrate (1.01 ml) are reacted to yield 17β-hydroxy-4-nitroandrost-4-en-3-one, m.p. 158°-160° C. (acetone-hexane)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C@@H:18]3[C:23]#[CH:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.[ClH:40]>C1(C)C=CC=CC=1.CCOCC>[ClH:40].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C@H:18]3[C:23]2[NH:39][N:38]=[N:37][CH:24]=2)[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:8]=1
Reactant: C#C[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3c2cnn[nH]2)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-ethynyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 98; 136 mg, 0.3 mmol) and trimethylsilylazide (0.1 ml, 0.8 mmol) in toluene were heated in a sealed tube at 130° C. for 48 hours. The mixture was allowed to cool and quenched with methanol and water. The mixture was concentrated in vacuo, and the residue purified by flash column chromatography, eluting with 5% methanol/dichloromethane. The debenzylated product was treated with 1.0 eq HCl in ether and the title compound isolated as a white crystalline solid (20 mg, 13%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[C:5]([C:14]#[N:15])=[C:4]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:3]=1[C:25]#[N:26].[H-].[Na+].C(#N)C.O.[CH:33]1(O)[CH2:36]C[CH2:34]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH:12]2[CH2:36][CH2:33][CH2:34]2)=[O:10])[C:5]([C:14]#[N:15])=[C:4]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:3]=1[C:25]#[N:26]
Reactant: OC1CCC1
Reactant: COC(=O)C(C)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C(=O)OC1CCC1)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
Methyl 2-[6-amino-4-(1,3-benzodioxol-5-yl)-3,5-dicyano-2-pyridinyl]propionate (from Example 6) (100 mg, 0.29 mmol) in cyclobutanol (5 ml) is heated under reflux with a catalytic amount of sodium hydride for 2.5 hours. The product is isolated by RP-HPLC (Kromasil column 250 * 20 mm, C18, 10 μm; acetonitrile/water gradient: 3 minutes 10%, then within 30 minutes to 80%, flow rate: 25 ml*min−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[CH2:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([CH2:21][CH3:22])=[CH:24][CH:25]=2)[C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCc1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(Br)c2)nc1
Product: CCc1ccc(CN(CCc2ccc(O)c(Br)c2)c2ncc(CC)cn2)cc1

Procedure:
Similarly prepared from N-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 4-ethyl benzyl bromide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and benzylamine
Reaction SMILES: C(OC([N:6]1[CH2:11][CH:10]([O:12][CH2:13][CH3:14])[O:9][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[N:7]1)=O)C.[OH-].[K+].C(O)C>O>[CH2:13]([O:12][CH:10]1[O:9][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[N:7][NH:6][CH2:11]1)[CH3:14]
Reactant: CCOC(=O)N1CC(OCC)OC(c2cccc(C(F)(F)F)c2)=N1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC1CNN=C(c2cccc(C(F)(F)F)c2)O1
Yield: 52 %

Procedure:
The crude 6-ethoxy-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxylic acid ethyl ester (17 g) from Step C above, was mixed with 12 g of KOH, 20 g of ethanol, and 40 g of water to create a reaction mixture. The reaction mixture was refluxed for 6 hours and then cooled. 50 ml of water was then added to the reaction mixture, followed by extraction with ethyl acetate (4×100 ml). The ethyl acetate extracts were conbined, dried (MgSO4) and the solvent removed, to give 7 g of crude 6-ethoxy-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine, which was not purified and was used in Step E below.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F.[C:9](O)(=[O:11])[CH3:10]>>[CH3:10][C:9]([C:4]1[CH:3]=[CH:2][C:1]([OH:7])=[CH:6][CH:5]=1)=[O:11]
Reactant: Oc1ccccc1
Reactant: CC(=O)O
Agent: F
Product: CC(=O)c1ccc(O)cc1
Yield: 61.6 %

Procedure:
Dann and Mylius in a dissertation included as part of a series of Reports from the Institute for Applied Chemistry of the University of Erlangen, received for publication on Jan. 7, 1954 and published in Annalen der Chemie 587 Band, pages 1 to 15, disclose the reaction of phenol and glacial acetic acid in the presence of hydrogen fluoride to produce 4-hydroxyacetophenone (4-HAP) in a yield of 61.6%. This reaction may be conventionally characterized as a Friedel-Crafts acetylation of phenol with acetic acid as the acetylating agent.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]>C(#N)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C@@:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CN1C(=O)[C@@]2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21

Procedure:
4′-Bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.32 g, 8.58 mmol) was resolved on a semi-preparative chiral column (CHIRALPAK-IA, Chiral Technologies, Inc.) eluted with 5% acetonitrile in tert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of the racemate dissolved in acetonitrile/tert-butylmethylether (1:1). (7R)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.14 g, 86%) was the first enantiomer to elute and was obtained as a crystalline colorless solid:. mp 226-228° C. (acetonitrile/tert-butylmethylether); 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.23 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 1H), 6.59 (s, 1H), 6.28 (s, 1H), 5.92-5.87 (m, 2H), 4.82 (d, J=9.7 Hz, 1H), 4.67 (d, J=9.7 Hz, 1H), 3.15 (s, 3H); MS (ES+) m/z 373.8, 375.8 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:7]1[CH:6]=[CH:5][C:4]([NH2:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(F)c1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 138 (25 g, 0.160 mol) in DMF (250 mL) at 0° C. was added dropwise a solution of NBS (28.5 g, 0.160 mol) in DMF (100 mL). The resulting mixture was stirred at 0° C. for 1 h and then at RT for another hour. After the completion of the reaction, the mixture was poured into water (4 L) and extracted with EtOAc. The combined organic layers were washed with water and brine solution, dried (Na2SO4), filtered and concentrated in vacuo to afford 34 g (90%) of 4-bromo-3-fluoro-2-nitro-phenylamine (140) as a yellow solid which was used without further purification.
Reaction SMILES: [O-]Cl=O.[Na+].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=[O:32].[Na+]>O.CC#N>[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[O:28][C:27]([C:29]([OH:32])=[O:30])=[CH:26][CH:25]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccc(C=O)o1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
A solution of NaClO2 (2.8 mmol) in 3 mL water was added dropwise to a stirred solution of 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furaldehyde (798 mg, 2.22 mmol) from step (a) in 3 mL MeCN, with cooling in an ice bath. After 2.5 h, the ice bath was removed, 2 mL more MeCN was added, and the two-phase liquid reaction mixture was stirred at room temperature for 25 h. The reaction mixture was diluted with water, made basic with saturated NaHCO3, and extracted with ethyl acetate (3×50 mL). The separated aqueous solution was acidified to pH 2 with 5% aqueous HCl and extracted with ethyl acetate (3×50 mL). This second ethyl acetate solution was washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness under vacuum to give the carboxylic acid (287 mg, 34%) which was used in the next step without further purification. The compound can be activated and esterified direct to a drug or further modified as described below.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([C@@H]([NH3+])C)C=CC=CC=1.S(=O)(=O)(O)O>C(O)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(=O)[O-]
Agent: C[C@H]([NH3+])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A sUspension of (S)-1-phenylethyl-ammonium (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoate (37.2 g, 77.5 mmol, 99.5% de) in aqueoUs isopropanol (50% strength, 90 ml) is admixed with 1N sulfuric acid (97 ml, 48.5 mmol) and stirred for 1 h at RT. The solid is filtered off with suction and dried to give (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid (26.5 g, 95%, >99.9% ee) as a colorless solid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([NH:32][C@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]2[N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:24]=1.[NH2:44][C:45]1[CH:54]=[C:53]2[C:48]([CH2:49][CH2:50][C:51](=[O:56])[N:52]2[CH3:55])=[CH:47][CH:46]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:44][C:45]2[CH:54]=[C:53]3[C:48]([CH2:49][CH2:50][C:51](=[O:56])[N:52]3[CH3:55])=[CH:47][CH:46]=2)=[O:28])=[C:25]([NH:32][C@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]2[N:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)[CH:24]=1
Reactant: O=C(O)c1ccc(Cl)cc1N[C@H]1CCCC[C@@H]1N1CCCC1
Reactant: CN1C(=O)CCc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3N[C@H]3CCCC[C@@H]3N3CCCC3)cc21

Procedure:
Hydrochloride of 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide (174 mg) and dimethylaminopyridine (21 mg) were added to a methylene chloride (5 mL) solution of 4-chloro-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoic acid (220 mg) and 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (100 mg). After stirring the reaction liquid overnight at room temperature, the reaction liquid was concentrated under a reduced pressure. By purifying the residue by silica gel column chromatography (hexane:ethyl acetate, 1:0 to 1:1), 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzamide was obtained as a pale yellow amorphous. By treating this with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzamide hydrochloride (212 mg) was obtained as an amorphous.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>CC(C)=O>[N:4]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][N:16]([CH3:17])[CH3:18])[CH:12]=[CH:13][CH:14]=1)=[C:1]=[S:3]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: S=C=S
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)Cc1cccc(OCCCN=C=S)c1

Procedure:
A solution of carbon disulphide (8.36 g) in acetone (16 ml) was added dropwise to a stirred solution of 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (20.8 g) in acetone (60 ml) at -10° to 0° during 15 minutes. A solution of mercuric chloride (27.2 g) in acetone (40 ml) was added slowly at -15° and after the addition the suspension was warmed to 0° and triethylamine (23 g) added dropwise. The suspension was refluxed for 45 minutes then filtered and evaporated to give an oil which was chromatographed (alumina, grade 3/ether). The appropriate eluate was evaporated to a yellow oil consisting of the title compound (8.7 g).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH:43][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:28])=[O:29])[CH:31]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: CN(C)CCNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 25 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 15 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 601 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([NH:22][CH3:23])[CH:21]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1>>[C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:21]=[C:20]([N:22]([CH3:23])[C:32](=[O:34])[CH2:31][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)[CH:19]=[N:18][CH:17]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: CN(C(=O)Cc1ccc(Cl)cc1)c1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1

Procedure:
The title compound was prepared according to the method described for Example 1 using (7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-methylamino-pyridin-3-yl)-methanone (Preparation 187) and (4-chloro-phenyl)-acetic acid to afford the title compound as off white solid in 45% yield, 21 mg.
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[C:27]([C:29]1[CH:38]=[C:37]2[C:32]([C:33]([CH3:41])([CH3:40])[CH2:34][CH2:35][C:36]2=[O:39])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:40][C:33]1([CH3:41])[C:32]2[CH:31]=[CH:30][C:29]([C:27]#[C:28][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:38][C:37]=2[C:36](=[O:39])[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: C#Cc1ccc2c(c1)C(=O)CCC2(C)C
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl )ethynyl]benzoate (Compound 1), 4 g (21.7 mmol) of 7-ethynyl-3,4-dihydro-4,4 -dimethylnaphthalen-1(2H)-one (Compound L) was converted into the title compound using 6 g (21.7 mmol) of ethyl 4-iodobenzoate, 5 g (7.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.4 g (7.2 mmol) of cuprous iodide.
Reaction SMILES: [OH2:1].[NH2:2][C:3]1[C:30]([Cl:31])=[CH:29][C:6]([C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:12][C@H:11]2[O:27][CH3:28])=[O:8])=[C:5]([O:32][CH3:33])[CH:4]=1>CO>[NH2:2][C:3]1[C:30]([Cl:31])=[CH:29][C:6]([C:7]([NH:2][C:3]2[CH:4]=[C:5]([O:32][CH3:33])[C:6]([C:7]([NH:9][C@H:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:12][C@H:11]3[O:27][CH3:28])=[O:8])=[CH:29][C:30]=2[Cl:31])=[O:1])=[C:5]([O:32][CH3:33])[CH:4]=1
Reactant: O
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)Nc1cc(OC)c(C(=O)N[C@H]2CCN(CCCOc3ccc(F)cc3)C[C@H]2OC)cc1Cl

Procedure:
40 Parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate was boiled in 160 parts of methanol. The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane. The product was filtered off, dried and recrystallized from 4-methyl-2-pentanone. The product was filtered off and dried (water-separator) yielding 18.5 parts of cis-4-amino-5-chloro-N-[2-chloro-4-[[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]aminocarbonyl]-5-methoxyphenyl]-2-methoxybenzamide; mp. 181.5° C. (compound 239).
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[CH2:7][C@H:8](O)[CH2:9][C@H:3]1[CH2:4][CH2:5]2.S(Cl)([Cl:13])=O.[OH-].[Na+].C(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:13][CH:8]1[CH2:9][CH:3]2[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]2)[CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: CN1[C@@H]2CC[C@H]1C[C@H](O)C2
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN1C2CCC1CC(Cl)C2
Reaction time: 8 h

Procedure:
To a solution of 95 g pseudotropine in 420 ml abs. CHCl3 are added dropwise at 0° 195 ml thionyl chloride within 20 minutes. The reaction mixture is refluxed for 4 hours, then left overnight at room temperature and then heated to 60°-65° for 3 hours. The mixture is then diluted with CH2Cl2 to a volume of ca. 100 to 150 ml and poured on ice-water. A 35% aqueous NaOH solution is added to a pH 11 and then dry ice to a pH 10. After extraction with CH2Cl2 and distillation of the extracts (second fraction~97°-98°) the title compound is obtained.