Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:35](Cl)=[O:36]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:33]=[C:32]([O:31][CH3:30])[C:40]([O:41][CH3:42])=[C:39]([O:43][CH3:44])[CH:38]=2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N[C@H]2C[C@@H](C(=O)N3CCN(c4ccccc4C#N)CC3)N(Cc3ccccc3)C2)cc(OC)c1OC
Yield: 17.9 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 3,4,5-trimethoxy-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (13.4 mg, 17.9%) as light yellow oil. MS m/e=583.7 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCc1ccccn1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: Clc1nccc(-c2cccc(CNCCc3ccccn3)c2)n1

Procedure:
Intermediate 1 was coupled with 2-pyridin-2-yl-ethylamine following procedure B. LC-MS showed the product had the expected M+H+ of 325.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(N3CCC4(CC3)OCCO4)nn2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
To a solution of 8-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane, prepared as in STEP 2 above (1.8 g, 6 mmol) in acetone/H2O (30 mL/30 mL) was added p-TSA.H2O (1.37 g, 7.2 mmol). The resulting mixture was stirred at 65° C. for 6 h and then concentrated to remove most of organic solvent. The residue was poured into CH2Cl2/H2O/Na2CO3(aq) (50 mL/25 mL/25 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layer was dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator to yield 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[NH:9][CH:8]=[CH:7]2)[CH3:2].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[C:11]2[C:6](=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CCOc1ccc2c(=O)[nH]ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOc1ccc2c(Cl)nccc2c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A suspension of 6-Ethoxy-2H-isoquinolin-1-one (896 mg, 4.74 mmol) in POCl3 (4 mL) was heated at 110° C. for 3 h (clear solution obtained upon heating). After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was poured into iced water (10 mL), pH was then adjusted to 10 with 3N NaOH and extracted with CHCl3 (3×25 mL). The combined CHCl3 layers were washed with brine and dried (MgSO4). The organic layer was then filtered and concentrated to give 1-chloro-6-ethoxy-isoquinoline (866 mg, 4.18 mmol, 88% yield, >90% pure) as tan solid. MS m/z 208 (M++H).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:27][CH:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[OH:26])[C:4]=2[CH2:3]1
Reactant: Fc1ccc(C2CO2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(F)cc2)CN(C)CC1
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) was dissolved in 5 mL DMF and sodium hydride (250 mg, 6.24 mmol) was added portionwise at 0° C. and the mixture stirred for 10 min. 2-(4-Fluoro-phenyl)-oxirane (450 mg, 3.26 mmol) was added dropwise at same temperature and stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water. The resultant solid was filtered and washed with water (100 mL) and hexane (100 mL), and the crude product was crystallized in EtOH:hexane (5:95 ratio) to obtain 300 mg of 2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-(4-fluoro-phenyl)-ethanol. 1H NMR (CDCl3, Free base) δ (ppm): 7.30 (m, 2H), 7.20 (d, 1H), 7.05 (m, 3H), 7.0 (d, 1H), 5.0 (t, 1H), 4.05 (d, 2H), 3.62 (d, 1H), 3.30 (d, 1H), 2.80 (m, 3H), 2.70 (m, 1H), 2.50 (s, 3H), 2.44 (s, 3H). Separation by chiral HPLC provided enantiomers 18a and 18b. Optical rotations: Compound No. 18a, (−) 6.97 (c 0.56, Chloroform, 89.35% HPLC purity); Compound No. 18b, (+) 13.03 (c 0.51, Chloroform, 99.51% HPLC purity).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:12])[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(O)(=O)C.Br>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH3:12])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)CCCc2ccc(F)cc2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(CCCc1ccc(F)cc1)c1cc(O)cc(O)c1
Reaction time: 17 h

Procedure:
Fifty grams of the above prepared 2-(3,5-dimethoxyphenyl)-5-(4-fluorophenyl)pentane, 450 ml. of acetic acid and 180 ml. of 48% HBr in water were mixed. While cooling, the mixture was saturated with hydrogen bromide gas (approximately 1/2 hour). The reaction was placed in an 87° bath and stirred for 17 hours. The reaction was then concentrated in vacuo and the residue neutralized with K2CO3 and NaHCO3, extracted with ether, treated with charcoal and MgSO4 and filtered to yield 45 g. of 2-(3,5-dihydroxyphenyl)-5-(4-fluorophenyl)pentane as a brown oil which distills at 180°/0.01 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])(=[O:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1ccc(F)cc1F)c1ccccc1

Procedure:
2,4-Difluoro-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2,4-difluorobenzenesulfonylchloride (94 mg, 0.455 mmol) according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 509.1; Calcd 509.11; 1H-NMR δ 77.71-7.46 (m, 6H), 7.25-7.17 (m, 1H), 7.03-6.96 (m, 2H), 6.72 (dd, 1H), 6.44 (d, 1H), 3.20-3.16 (m, 8H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[N:11]=1>C(#N)C>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5](=[S:6])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][C:5](=[S:6])[NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])[N:11]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1cccc(CO)n1
Solvent: CC#N
Product: FC(F)(F)CNC(=S)Nc1cccc(COC(=S)NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 19.7 %

Procedure:
2,2,2-Trifluoroethylisothiocyanate (2.82 g.) was added to a solution of 2-amino-6-hydroxymethylpyridine (2.1 g.) in acetonitrile (20 ml.) and the solution kept at room temperature for 18 hours and then evaporated to dryness. The residue was partitioned between ethyl acetate and water and the ethyl acetate phase separated, dried and evaporated to dryness. The residue was recrystallised from ethanol to give 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-[N-(2,2,2-trifluoroethyl)-thiocarbamoyloxymethyl]pyridine (0.8 g.), m.p. 173°-175°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1([C@@H]2[O:40][CH:39]([CH2:41][O:42][NH2:43])[CH2:38][CH2:37][O:36]2)C=CC=CC=1>>[OH:40][C@@H:39]([CH2:38][CH2:37][OH:36])[CH2:41][O:42][NH:43][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: NOCC1CCO[C@H](c2ccccc2)O1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@@H](O)CCO)c(=O)n(C)c1=O
Yield: 87 %

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with O—((S)-2-Phenyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine, followed by acid hydrolysis of the resulting material (total yield 87%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (s, 1H) 11.97 (s, 1H) 7.80 (dd, J=10.11, 1.77 Hz, 1H) 7.58 (d, J=8.84 Hz, 1H) 7.15 (t, J=8.59 Hz, 1H) 4.90 (d, J=4.29 Hz, 1H) 4.38 (t, J=5.05 Hz, 1H) 3.74-3.86 (m, 2H) 3.56-3.66 (m, 1H) 3.45-3.53 (m, 2H) 3.21 (s, 3H) 2.96 (s, 3H) 1.35-1.56 (m, 2H). [M+H] calc'd for C17H20FIN4O6, 523. found, 523.
Reaction SMILES: C([C:3]1[CH:7]=[CH:6][O:5][N:4]=1)=O.[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20]C3OC=NC=3)[CH2:18][C@@H:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]([S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])[CH2:15][C:14]=2[CH:41]=1)#[N:9].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20][C:6]3[O:5][N:4]=[CH:3][CH:7]=3)[CH2:18][C@@H:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]([S:33]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:35])[CH2:15][C:14]=2[CH:41]=1)#[N:9]
Reactant: CN(C)CCS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2cnco2)C[C@H]1Cc1ccccc1
Reactant: O=Cc1ccon1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2ccno2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-formylisoxazole (19.4 mg, 0.2 mmol) and Compound B of Example 25 (39.9 mg, 0.1 mmol) in DCM (0.5 mL) at rt was added TFA (45 mg, 0.4 mmol), followed by triethylsilane (35 mg, 0.3 mmol). The resulting mixture was stirred at rt for 1 hour, neutrallized with NaHCO3 solution and extracted with DCM (2×5 mL). The combined extract was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (SiO2; ethyl acetate: methanol ammonia/100:10:0.1) to afford the title compound, 45 mg (87%). MS: m/e (M+H)+=480.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH:13](N)=[O:14]>O>[CH:13]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[CH2:9]1)=[O:14]
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: NC=O
Agent: Br
Solvent: O
Product: O=CN1CCc2cc(O)ccc2C1
Temperature: 100 °C

Procedure:
46.0 g of 1,2,3,4-tetrahydro-6-hydroxy-isoquinoline-hydrobromide are reacted with 85 ml of formamide for 1 hour at 140° C. with stirring. After cooling to 100° C., 216 ml of water are added, whereby the reaction product crystallizes. 34.0 g of 2-formyl-1,2,3,4-tetrahydro-6-hydroxy-isoquinoline are obtained. m.p. = 185.5° - 186° C. (ethanol).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49]([C:52](OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]([CH2:51][CH3:50])[CH2:47][CH2:48][NH:49][CH3:52])[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN(CC)CCNC)c3)c2)c1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate (0.130 g, 0.16 mmol) in DCM (200 μL) was added TFA (100 μL, 0.1298 mmol) after which the mixture was stirred at room temperature for ¼ h. The reaction mixture was concentrated under vacuum, purified using a Gilson HPLC (with 0.1% TFA), and product concentrated using a GeneVac EZ-2 evaporator at 45° C. for 8 h. Extra TFA was removed by re-dissolving the resultant mixture in DCM and passing it though an amino cartridge to afford 0.0555 g (48%) of the title compound. LC-MS m/z 716 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.39 (t, J=7.53 Hz, 3H) 1.48 (t, J=7.28 Hz, 3H) 1.80-1.95 (m, 2H) 2.08 (d, J=12.30 Hz, 2H) 3.15 (q, J=7.53 Hz, 2H) 3.57 (s, 8H) 3.62-3.72 (m, 2H) 4.02 (dd, J=8.41, 3.14 Hz, 2H) 4.27-4.39 (m, 1H) 4.43-4.52 (m, 4H) 4.64 (s, 2H) 4.70 (s, 2H) 7.35-7.46 (m, 2H) 7.46-7.63 (m, 4H) 7.65 (s, 1H) 7.73 (d, J=7.53 Hz, 1H) 7.81 (s, 1H) 8.05 (d, J=7.78 Hz, 2H) 8.27 (s, 1H) 8.40 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[C:7]([N+:19]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH2:19])[C:8]([N:11]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:18])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCN(C)c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(4-tert-Butyl-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Step 2, 200 mg, 0.682 mmol) was dissolved in 7 mL MeOH. Palladium (66 mg, 0.062 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding the title compound as a dark brown solid. MS (M+H)+=264; Calc'd 263.42 for C16H29N3.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]([CH3:13])([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:9][C:8](=[O:10])[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)([CH3:13])[CH2:11][CH3:12])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(C)(Oc1ccc(C)cc1)C(=O)O
Product: CCC(C)(Oc1ccc(C)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 85 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 600 mg of (2RS)-2-(4-methylphenoxy)-2-methylbutyric acid and 1.32 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-napthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.51 g of the title compound as a colorless foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:20][N:19]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C@H:18]([CH2:49][C:50]([CH3:55])([CH3:54])[C:51]([OH:53])=O)[CH2:17]2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:20][N:19]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[C@H:18]([CH2:49][C:50]([CH3:55])([CH3:54])[C:51]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:53])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN1CCNCC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)N4CCN(C)CC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 102, 1-methylpiperazine is reacted with 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) to afford 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-1-(4-methyl-piperazin-1-yl)-propan-1-one which is subsequently deprotected according to general procedure A to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[S:8][C:7]=2[CH:15]=1)#[N:2].CO.[OH-].[Na+]>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:7]=2[CH:15]=1)#[N:2]
Reactant: COC(=O)c1cc2ccc(C#N)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2cc(C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with methyl 6-cyanobenzo[b]thiophene-2-carboxylate (4.00 g, 17.9 mmol), methanol (130 mL), and sodium hydroxide (23 g, 0.58 mol) in water (200 mL). The reaction was stirred at room temperature for 20 minutes. The reaction was concentrated to half of the volume and acidified with 6 N aq. HCl. The mixture was extracted with CHCl3/i-PrOH (90:10) and the organic phase was concentrated under reduced pressure to get the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([C:19]1[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24]([C:22]2[S:23][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:20][CH:21]=2)=[O:25])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)s1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (40 mg) and 5-(methylsulfonyl)thiophene-2-carboxylic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(methylsulfonyl)thiophene-2-carboxamide. MS (Q1) 393.0 (M)+.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>C(O)C>[OH:27][CH2:26][CH:25]([NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7])[CH2:28][OH:29]
Reactant: NC(CO)CO
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Solvent: CCO
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NC(CO)CO)c(O)c2c1
Yield: 114.3 %

Procedure:
0.035 gm of 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 0.088 g of 2-amino-propane-1,3-diol were dissolved in 1 ml of ethanol and the mixture was refluxed for 24 h. The reaction mixture was concentrated and the residue was dissolved in 10 ml of ethyl acetate. The ethyl acetate solution was extracted with 5 ml of aqueous 1 M HCl and water, dried (sodium sulfate) and concentrated to give 0.042 g of a white solid: MS-(+)-ion: 355.1.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:22]([C@@:23]4([CH3:29])[CH2:24][CH2:25][C@H:26]([OH:28])[CH2:27][C:2]124)[CH2:21][CH2:20][C@@:19]1([CH3:30])[C@H:6]3[CH2:7][CH2:8][C@:9]1([OH:31])[C@H:10]([CH3:18])[CH2:11][CH2:12][C@@H:13]([CH3:17])[CH:14]([CH3:16])[CH3:15].[NH2:32][CH2:33][CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1.C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:27][C@@H:26]([OH:28])[CH2:25][CH2:24][C@:23]1([CH3:29])[C@@H:22]1[C@H:5]([C@H:6]3[C@:19]([CH3:30])([CH2:20][CH2:21]1)[C@@:9]([OH:31])([C@H:10]([CH3:18])[CH2:11][CH2:12][C@@H:13]([CH3:17])[CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:32][CH2:33][CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)[C@H](C)CC[C@@H](C)[C@@]1(O)CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@@]21C
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)[C@H](C)CC[C@@H](C)[C@@]1(O)CC[C@H]2[C@@H]3C[C@@H](NCCc4c[nH]cn4)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Yield: 13 %

Procedure:
5,6α-epoxicampestane-3β,17-diol (6.8 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give (5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-campestane-3β,17-diol) as a white solid (5.7 g, 49%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 13% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH3:25])=[C:14]([Cl:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Product: CCOCc1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 5, intermediate from (4R,9aR)-6-ethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.