Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[N+:9]([C:12]1[CH:13]=[C:14]([C:22](Cl)=[O:23])[C:15]2[O:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)([O-:11])=[O:10].O>C(C(C)=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][N:2]([NH:1][C:22]([C:14]2[C:15]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[O:23])[CH2:3][CH2:4]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2c1OCCO2
Reactant: CN1CCN(N)CC1
Solvent: O
Solvent: CCC(C)=O
Product: CN1CCN(NC(=O)c2cc([N+](=O)[O-])cc3c2OCCO3)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
33 g of 1-amino-4-methylpiperazine was dissolved in 630 ml of methyl ethyl ketone. The mixture was cooled to 10° C. and 61 g of 7-nitro-1,4-benzodioxane-5-carbonyl chloride were introduced by portions. The mixture was stirred for two hours and then the solid was filtered off and washed with 150 ml of methyl ethyl ketone. The obtained product was purified by transformation into the base (M.P.: 212° C.) and recrystallized by treatment with hydrochloric ethanol. 45 g of N-(4-methyl-1-piperazinyl)-7-nitro-1,4-benzodioxane-5-carboxamide were obtained (M.P.: 210° C. with one mole of water). The structure was confirmed by nuclear magnetic resonance and infrared analyses.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH:7]=[CH:6]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C>ClCCCl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:7]=[CH:6]3)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccccc1CNc1ccc2cc(CN)ccc2n1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccccc1CNc1ccc2cc(CNCc3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 53.2 %

Procedure:
A solution of (6-aminomethyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 85, step B) (390 mg, 1.33 mmol), 4-fluorobenzaldehyde (181.5 mg, 1.46 mmol) and acetic acid (319.3 mg, 5.32 mmol) in 1,2-dichloroethane (15 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-boron hydride (657 mg, 2.79 mmol) was added, the reaction mixture was allowed to stir for 60 h at room temperature, poured into ice/saturated NaHCO3 solution (30 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as colorless oil (284 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([C:30]3([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:37].CO>C(OCC)C>[ClH:1].[ClH:37].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([C:30]3([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(-c3ccc(Cl)c(Cl)c3)c2)C2(O)CCCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OC1(C(CN2CCNCC2)c2cccc(-c3ccc(Cl)c(Cl)c3)c2)CCCCC1
Reaction time: 18 h
Yield: 81 %

Procedure:
tert-butyl 4-[2-(3′,4′-dichloro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (0.39 g 0.73 mmol) was dissolved in diethyl ether (15 mL) then a 2N ethereal solution of hydrochloric acid (10 mL) was added. Methanol (approximately 1 mL) was then added until the resulting precipitate dissolved, and the homogeneous solution was stirred for 18 h. The precipitated product was collected by filtration, washed with diethyl ether and dried in a vacuum oven at 50° C. to yield 0.28 g (81%) of 1-[1-(3′,4′-dichloro-1,1′-biphenyl-3-yl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride as a white solid. MS (ESI) m/z 433/435/437 ([M+H]+); HRMS: calcd for C24H30N2OCl2.2.00 HCl, 433.1813; found (ESI), 433.1813.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C([O-])=O.[C:32]([C:34]1[C:35]([CH3:51])=[C:36]([C@@H:41]2[O:46][CH2:45][C@@H:44]3[CH2:47][NH2+:48][CH2:49][CH2:50][N:43]3[CH2:42]2)[CH:37]=[CH:38][C:39]=1[F:40])#[N:33].[N:52]1([C:57]2[N:62]=[CH:61][C:60]([CH2:63][C:64](O)=[O:65])=[CH:59][N:58]=2)[CH:56]=[N:55][N:54]=[N:53]1.C(N(CC)CC)C>CN(C=O)C>[F:40][C:39]1[C:34]([C:32]#[N:33])=[C:35]([CH3:51])[C:36]([C@@H:41]2[O:46][CH2:45][C@@H:44]3[CH2:47][N:48]([C:64](=[O:65])[CH2:63][C:60]4[CH:59]=[N:58][C:57]([N:52]5[CH:56]=[N:55][N:54]=[N:53]5)=[N:62][CH:61]=4)[CH2:49][CH2:50][N:43]3[CH2:42]2)=[CH:37][CH:38]=1
Reactant: O=C(O)Cc1cnc(-n2cnnn2)nc1
Reactant: Cc1c([C@H]2CN3CC[NH2+]C[C@H]3CO2)ccc(F)c1C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
HATU (192 mg, 0.504 mmol) was added to a solution of (3S,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium trifluoroacetate (104 mg, 0.504 mmol) in DMF (1.5 mL). The reaction mixture was stirred at RT for 15 minutes and a solution of [2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetic acid (284 mg, 0.564 mmol) and triethylamine (0.37 ml, 2.65 mmol) in DMF (1 mL) was added. The flask was rinsed with DMF (0.5 mL). The solution was stirred at RT overnight then diluted with EtOAc and washed with dilute NaHCO3 solution, water (3×) and brine, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by silica gel chromatography (24 g cartridge) using CH2Cl2 (A) and CH2Cl2:MeOH 90:10 (B) with gradient elution from 100% A to 100% B over 12 column volumes and holding at 60% A for 2 column volumes to afford the title compound: LC/MS: 505 (M+CH3CN+Na), 464 (M+H). The title compound was converted to its hydrochloride salt by dissolving in methylene chloride and adding 1 equivalent 1M HCl in ether. The suspension was stirred at RT for 30 minutes and the solvent evaporated: NMR 500 MHz (CD3OD(mixture amide rotamers) 10.03 (s, 1H); 8.87 (s, 1H); 8.86 (s, 1H); 7.94 (q, 1H); 7.31 (d t, 1H); 5.08-5.15 (m, 1H); 54.68 (d, 0.5H); 4.60 (d, 0.5H); 4.01-4.38 (m, 5.5H); 3.82 (t, 2H); 3.58-3.71 (m, 1.5H); 3.40-3.53 (m, 2.5H); 3-31-3.37 (m, 1.5H); 2.61 (br s, 3H); LC/MS 527 (M+Na+CH3CN), 505 (M+H+CH3CN), 486 (M+Na), 464 (M+H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([NH:15][NH:16][C:17](=O)[CH:18]([CH3:20])[CH3:19])=O)=[CH:11][N:10]=[C:9]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C(#N)C>[CH:1]1([NH:6][C:7]2[C:8]3[CH:24]=[N:23][N:22]([CH2:25][CH3:26])[C:9]=3[N:10]=[CH:11][C:12]=2[C:13]2[S:36][C:17]([CH:18]([CH3:20])[CH3:19])=[N:16][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(=O)C(C)C)cnc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC#N
Product: CCn1ncc2c(NC3CCCC3)c(-c3nnc(C(C)C)s3)cnc21
Temperature: 65 °C

Procedure:
Intermediate 10 was dissolved in acetonitrile (5 ml) then treated with Lawesson's reagent (0.125 g) and heated under nitrogen at 65° C. for 66 h. Volatiles were removed in vacuo and the residue was purified by mass directed autoprep HPLC to afford Example 6. LCMS showed MH+=357; TRET=3.59 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:9]1[N:8]2[C:4]([CH2:3][NH:2][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:5][N:6]=[C:7]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CN)nnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)c3ccccc3)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
The mixture of 3-(aminomethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one hydrochloride (160 mg, 0.51 mmol), [B] benzoic Acid (0.069 g, 0.56 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.25 g, 0.56 mmol) and triethylamine (0.21 mL, 1.5 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was purified by preparative LCMS to yield the desired product (150 mg, 77%). LCMS calculated for C19H22N7O2 (M+H): 380.2. Found: 380.2.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[NH:15][C:16](=[O:19])[CH2:17][Br:18].C(Cl)Cl>C(N(CC)CC)C>[C:1]1([S:7]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[NH:15][C:16](=[O:19])[CH2:17][Br:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)Nc1cccc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)Nc1cccc(OS(=O)(=O)c2ccccc2)c1

Procedure:
To a mixture of 4.4 g. of benzene sulfonyl chloride and 5.7 g. of 3'-hydroxy bromoacetanilide in 100 ml. of methylene chloride is added dropwise 2.6 g. of triethylamine. The product is recovered by washing with cold water, drying and removal of the solvent. There is obtained 9.0 g. of the title compound, nD30 = 1.5830.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([NH2:17])[CH2:15][NH2:16]>C(Cl)Cl>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][CH2:15][CH2:14][NH2:17]
Reactant: COc1ccc2nccc(Cl)c2n1
Reactant: NCCN
Solvent: ClCCl
Product: COc1ccc2nccc(NCCN)c2n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 8-chloro-2-methoxy-[1,5]naphthyridine (commercial; 1.7 g, 8.80 mmol) and ethane-1,2-diamine (1.2 mL, 2 eq.) was heated slowly to 80° C. over 1 h and subsequently up to 100° C. for 2 h. After cooling to rt, the yellow solution was taken up in DCM and successively washed with sat. aq. NaHCO3. The org. layer was concentrated under reduced pressure to afford the title intermediate as a pale yellow oil (981 mg, 51% yield).
Reaction SMILES: I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I([Cl:16])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:28][O:29][C:30]([C:32]1[C:37]([Cl:38])=[C:36]([Cl:39])[C:35]([Cl:40])=[C:34]([C:41]2[O:42][CH:43]=[CH:44][CH:45]=2)[N:33]=1)=[O:31]>C(O)(=O)C.C(OCC)C>[Cl:38][C:37]1[C:32]([C:30]([O:29][CH3:28])=[O:31])=[N:33][C:34]([C:41]2[O:42][C:43]([Cl:16])=[CH:44][CH:45]=2)=[C:35]([Cl:40])[C:36]=1[Cl:39]
Reactant: COC(=O)c1nc(-c2ccco2)c(Cl)c(Cl)c1Cl
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1nc(-c2ccc(Cl)o2)c(Cl)c(Cl)c1Cl
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Benyltrimethylammonium tetrachloroiodate (292 mg, 0.70 mmol) was added to a solution of methyl-3,4,5-trichloro-6-(2-furyl)pyridine-2-carboxylate (101 mg, 0.33 mmol) in acetic acid (5 mL). After one hour, the suspension was diluted with diethyl ether and the organic mixture was washed with 0.1 N sodium thiosulphate, 0.1 N sodium bicarbonate and dried (MgSO4). The residue was purified by column chromatography (diethyl ether:hexane, 5:95) to give methyl 3,4,5-trichloro-6-(5-chloro-2-furyl)pyridine-2-carboxylate (58 mg, 0.17 mmol): 1H NMR (CDCl3): δ 7.41 (d, J=3.6 Hz, 1H), 6.40 (d, J=3.6 Hz, 1H), 4.05 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([F:14])[C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([F:14])[C:10](=[O:11])[NH:9][C:7]1=[O:8])(=[O:17])[CH3:16]
Reactant: O=c1[nH]c(=O)n(COCCO)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCOCn1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-Hydroxyethoxy)methyl-5-fluorouracil (1 g) prepared in Example 1 was dissolved in a mixture of acetic anhydride (5 ml) and pyridine (5 ml) and the solution was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting oil was extracted with chloroform (30 ml). The extract was washed with hydrochloric acid, aqueous sodium bicarbonate and then water, dried over magnesium sulfate and the solvent was evaporated off under reduced pressure. The residue was treated with methanol to give 0.9 g of crystalline 1-(2-acetoxyethoxy)methyl-5-fluorouracil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)(=[O:35])=[O:34])[CH:27]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]2[S:37][C:38]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:39][CH:40]=2)(=[O:34])=[O:35])[CH:27]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(Nc1cccnc1)c1ccc(Br)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid pyridin-3-ylamide [CAS-No. 439934-18-6] (160 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as a yellow solid (200 mg, 67%). MS (ISN) 592.1 [(M−H)−]; mp 248° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([Cl:30])=[C:22]([Cl:31])[CH:21]=4)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=3)=[CH:7][CH:6]=2)[CH2:2]1.C(N(CC)CC)C.[N:39]([CH3:42])=[C:40]=[O:41]>CN(C=O)C>[Cl:31][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH:3]4[CH2:4][N:1]([C:40]([NH:39][CH3:42])=[O:41])[CH2:2]4)=[CH:6][CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[Cl:30]
Reactant: FC(F)(F)c1cc(C2(C(F)(F)F)CC(c3ccc(C4CNC4)cc3)=NO2)cc(Cl)c1Cl
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)N1CC(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(C(F)(F)F)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(4-(azetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0.05 mmol) was dissolved in DMF (1 mL); triethylamine (0.20 mmol) was added, followed by a solution isocyanatomethane. The resulting solution was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the crude product purified by preparative HPLC to give 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-N-methylazetidine-1-carboxamide (11.2 mg) MH+ 540.1; retention time 6.14 minutes.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1>O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:4][CH2:3][CH2:2][OH:5])=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: OCCO
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: [Na]
Solvent: O
Product: COc1ccc2c(OCCO)ccnc2c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
In a 1 L RBF under nitrogen was placed sodium (15 g, 652 mmol) cubes. The flask was cooled in an ice bath and ethane-1,2-diol (150 ml, 2690 mmol) was added slowly through an addition funnel (15 min). The cooling bath was removed and the reaction mixture was allowed to warm to 50° C. until all the sodium disappeared. After 20 min, the mixture was heated to 110° C. and 4-chloro-7-methoxyquinoline (69 g, 356 mmol) was added. After 12 h, the mixture was cooled to room temperature and was diluted with H2O (250 mL), resulting the formation of a thick sludge. The content was filtered, and washed with H2O (2×50 mL). After air drying overnight, the solid was heated with benzene (300 mL) under reflux for 3 hr. The mixture was cooled and filtered. The solid was washed with ether (2×50 mL) to give a soft solid (77 g) contaminated with the small amount of bisether dimer. MS (ESI pos. ion) calcd for C12H13NO3: 219.2; found: 220.1 (MH+). 1H NMR (400 MHz, Chloroform-d) δ ppm 3.94 (s, 3H) 4.13 (t, 2H) 4.32 (t, 2H) 6.64 (d, J=5.28 Hz, 1H) 7.14 (dd, J=9.19, 2.54 Hz, 1H) 7.37 (d, J=2.35 Hz, 1H) 8.08 (d, J=9.19 Hz, 1H) 8.66 (d, J=5.48 Hz, 1H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([C:15]#[C:16][CH2:17][OH:18])([OH:14])[C@@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10](/[CH:15]=[CH:16]\[CH2:17][OH:18])([OH:14])[C@@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@](O)(/C=C\CO)[C@@H]1c1ccccc1
Reaction time: 4 h

Procedure:
Palladium on calcium carbonate, poisoned with lead (Lindlar catalyst, 2 g) was added to a solution of (2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1yl)-2-phenylpiperidin-3-ol (Preparation 7; 32 g, 96.6 mmol) in ethyl acetate (300 ml) and the mixture was stirred under hydrogen (1 atmosphere) for 4 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil to (32 g, 100%). 1H NMR (360 MHz, CDCl3)δ 7.42 (2H, d, J=7.6 Hz), 7.35-7.25 (3H, m), 5.83 (1H, d, J=12.3 Hz), 5.68 (1H, dt, J=12.3, 6.0 Hz), 5.06 (1H, s), 4.27 (1H, m), 4.12 (2H, m), 3.32 (1H, m), 3.13 (1H, s), 2.28 (1H, t, J=5.9 Hz), 2.02 (1H, m), 1.92-1.78 (3H, m), and 1.32 (9H, s). m/z (ES+) 334 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6]C(OCC2C=CC=CC=2)=O)[CH2:4][N:3]1[C:17]([NH:19][S:20]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=[O:22])=[O:21])=[O:18].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[H][H].N1CCC1=O>C(#N)C.[Pd]>[NH2:6][C@H:5]1[CH2:4][N:3]([C:17]([NH:19][S:20]([NH:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)(=[O:22])=[O:21])=[O:18])[C:2]1=[O:1]
Reactant: [H][H]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Nc2ccncc2)C1=O)OCc1ccccc1
Agent: [Pd]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C1CCN1
Solvent: CC#N
Product: N[C@H]1CN(C(=O)NS(=O)(=O)Nc2ccncc2)C1=O
Reaction time: 0.5 h

Procedure:
(S)-2-Oxo-3-[[(phenylmethoxy)carbonyl]amino]-N-[[(4-pyridyl)amino]sulfonyl]-1-azetidinecarboxamide (2.1 g; see example 36) was suspended in 25 ml of acetonitrile and 3 g (3.6 ml) of bis(trimethylsilyl)acetamide was added with stirring. After a few minutes a clear solution was formed. This solution was added to a suspension of 1 g of 10% palladium on charcoal in 25 ml of acetonitrile, through which hydrogen was passed for 30 minutes prior to the addition of the solution of the starting azetidinone. Hydrogenation was complete after 70 minutes. The catalyst was removed by filtration. On addition of 1 ml of methanol the title compound crystallized from the solution; yield 1.0 g.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:49][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:40][CH:41]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
A solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (59 mg, 0.088 mmol) in DCM (2 ml) was treated with TFA (0.6 ml, 7.6 mmol) and the mixture was stirred at rt for 12 h. The solvent was removed in vacuo to provide the title compound as a white solid (40 mg, 0.065 mmol, 74.0% yield). LCMS: m/e 615.7 (M+H)+, 2.00 min (method 7). 1H NMR (400 MHz, MeOD) δ ppm 7.94 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 5.33 (d, J=4.8 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.73-3.42 (m, 4H), 3.33 (m, 1H), 2.99-2.94 (m, 1H), 2.93 (s, 6H), 2.53 (td, J=10.6, 5.6 Hz, 1H), 2.99-1.29 (m, 2H), 1.98-1.22 (m, 20H), 1.76 (s, 3H), 1.20 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.99 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2)[CH3:2].Cl[C:19]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=[C:21]([S:30][CH3:31])[N:20]=1.C(N(CC)CC)C>C(O)CCC>[CH2:28]([O:27][C:25]([C:24]1[C:19]([N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)=[N:20][C:21]([S:30][CH3:31])=[N:22][CH:23]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)CCNc1ccc2c(c1)CCC2
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCOC(=O)CCN(c1ccc2c(c1)CCC2)c1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.2 %

Procedure:
To a solution of 3-(indan-5-ylamino)-propionic acid ethyl ester (5 g, 21.4 mmol) and ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (5 g, 21.4 mmol) in 40 mL of n-butanol was added triethylamine (3 mL, 21.4 mmol). The solution was stirred at rt for 2 days. The solvent was removed under vacuum. The residue was extracted into EtOAc, washed with water, brine and then dried with Na2SO4. Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:10-1:6, v/v), gave 8.2 g (90%) of the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.22 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 6.87 (d, J=7.6 Hz, 1H), 4.35 (t, 2H), 4.06 (q, 2H), 3.55 (q, 2H), 2.82 (m, 4H), 2.69 (t, 2H), 2.58 (s, 3H), 2.06(m, 2H), 1.20 (t, 3H), 1.02 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[N:11][N:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)[C:9]2[CH:10]=[N:11][N:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)cnn1C1CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)cnn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-1H-pyrazole-5-carboxylate (Step 34.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.78 min (HPLC 1); tR: 1.10 min (LC-MS 2); ESI-MS: 441 [M+H]+ (LC-MS 2); Rf=0.31 (EtOAc).