Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.3 %

Procedure:
Add a suspension of pre-washed NaH (0.1 g, 2.48 mmol, 60% dispersion in mineral oil) in THF (2 mL) to an ice cold solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.48 mmol) in dry THF (3 mL). Allow mixture to stir for 20 minutes, then add 2-chloro-5-nitro-pyridine (0.36 g, 2.26 mmol) in portions. After addition is completed, remove cooling bath and stir the reaction mixture at 22° C. overnight. Cool reaction mixture with ice bath and add a saturated aq. sodium bicarbonate solution (5 mL). Distribute the reaction mixture between ethyl acetate (25 mL) and distilled water (25 mL). Isolate the aqueous phase and extract with ethyl acetate (3×35 mL). Dry the combined organic phases over sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to give 4-(5-Nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (0.55 g, 75% yield). MS(ES): m/z=324.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][CH:29]=2)=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:16]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[NH:1][C:39](=[O:41])[N:23]2[C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)[nH]c3c(N(Cc4ccccc4)Cc4ccccc4)ncnc32)c1
Reaction time: 1 h
Yield: 143.5 %

Procedure:
A solution of tert-butyl 3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenylcarbamate (3) (4.0 g, 8.1 mmol) and TEA (2 mL, 14.5 mmol) in 80 mL dry DCM was cooled to 0° C. under N2, triphosgene (1.2 g, 4.0 mmol) in 10 mL dry DCM was added dropwise during 2 hrs. After additional 1 hr stirring, the reaction was quenched with water (100 mL). The organic layer was separated, washed with water (100 mL×2) and brine (100 mL×1), dried over Na2SO4, then concentrated to dryness in vacuo. tert-Butyl 3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (4) (3.0 g, 71%) was obtained as a brown solid. LC-MS (ESI): m/z (M+1) 523.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:23]=[C:24]([NH2:26])[N:25]=3)[CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.[N:33]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:23]=[C:24]([NH:26][C:44](=[O:45])[C:43]4[CH:47]=[CH:48][C:40]([CH2:39][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:41][CH:42]=4)[N:25]=3)[CH:22]=2)=[CH:4][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc(CN2CCCCC2)cc1
Reactant: COc1cc(-c2ccc3nc(N)nn3c2)ccc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2ccc3nc(NC(=O)c4ccc(CN5CCCCC5)cc4)nn3c2)ccc1OCc1ccccc1
Yield: 9.1 %

Procedure:
To a reaction vessel containing the 6-{3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (104 mg, 0.3 mmol, 1 equivalent) and pyridine (0.063 mL, 1.2 mmol, 4 eq.) in dichloromethane (1 mL) was added 4-piperidin-1-ylmethyl-benzoyl chloride (142 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2 mL), dropwise. The vessel was capped and heated to reflux for approximately 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give N-[6-(4-benzyloxy-3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-piperidin-1-ylmethyl-benzamide as a white solid (14.9 mg, 9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[CH3:16]>S1(CCCC1)(=O)=O>[C:15]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:21][CH2:20]1)(=[O:17])[CH3:16]
Reactant: Brc1cccc(Br)n1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(=O)NC1CCN(c2cccc(Br)n2)CC1
Temperature: 150 °C
Reaction time: 20 h
Yield: 56 %

Procedure:
A mixture of 0.042 mole of 2,6-dibromopyridine, 0.056 mole of anhydrous potassium carbonate and 0.052 mole of 4-acetamidopiperidine in 75 ml of sulfolane is heated to 150° C. with stirring for 20 hours, then the sulfolane is concentrated to 1/5th of its volume, the reaction mixture is poured in 100 ml of water and extracted with diethyl ether (4×150 ml). The organic phase is washed with water, dried over anhydrous sodium sulfate, concentrated to dryness and the residue is crystallised in 40 ml of ethyl acetate. The 4-acetamido-1-(6-bromo-2-pyridyl)piperidine is thus obtained; m.p. 158° to 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[N:31]#[C:32]Br>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[N:29][C:32]#[N:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: N#CBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=NC#N)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl sulfoximide (50 mg, 0.000108 mol) and DMAP (14.5 mg, 0.000216 mol) in DCM (1 mL) was added cyanogen bromide (23 mg, 0.000216 mol) at 25° C. Reaction mixture was stirred at 25-30° C. for 18 hr and then diluted with DCM (10 mL). Organic layer was washed with dil.HCl. Drying over sodium sulfate and evaporation afforded 20 mg of titled compound in 37% yield.
Reaction SMILES: CCN(C1C=CC2C3(C4C(OC=2C=1)=CC(C)=C(NC1C=CC=CC=1)C=4)OC(=[O:20])C1C3=CC=CC=1)CC.P([O-])([O-])([O-])=O.[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:70])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:69])[CH2:64][C@H:65]([OH:68])[C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48].C(Cl)Cl>C(O)C>[CH3:42][C@@H:43]([C@@H:50]1[C@@:54]2([CH3:70])[CH2:55][CH2:56][CH2:57]/[C:58](=[CH:59]\[CH:60]=[C:61]3\[CH2:62][C@@H:63]([OH:69])[CH2:64][C@H:65]([OH:68])[C:66]\3=[CH2:67])/[C@@H:53]2[CH2:52][CH2:51]1)[CH2:44][CH2:45][CH2:46][C:47]([OH:20])([CH3:48])[CH3:49]
Reactant: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc(C)c(Nc3ccccc3)cc1C21OC(=O)c2ccccc21
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Reaction time: 48 h

Procedure:
Nocardia autotrophica N-102 in the same BG medium (100 ml/500 ml-Erlenmeyer flask) as used in Example 1 was cultured at 28° C. under the aerobic conditions for 48 hours. To the culture medium were added 10 ml of a 5% PMCD solution (0.01 M phosphate buffer, pH 7.0) and a solution of 0.1% 1α-hydroxyvitamin D3 in 1 ml of ethanol (in the amount of 140 mol of PMCD relative to 1 mol of 1α-hydroxytvitamin D3). After cultivation for a further 2 hours, methylene chloride was added to the flask, and analysis was carried out according to the method as described in Example 3. The peak fraction having a retention time of 12 minutes was collected, concentrated at 40° C. or below under reduced pressure and applied to HPLC on Zorbax ODS column (4.6 mm×25 cm, made by Du Pont Co., USA) with water-methanol (1:9) as a mobile phase at a flow rate of 1.0 ml/min. After elution, the peak fraction having a retention time of 5.6 minutes was collected and concentrated to dryness at 40° C. or below under reduced pressure with a nitrogen gas replacement to give 650 μg (65% of the conversion ratio from the material) of 1α,25-dihydroxyvitamin D3. On the other hand, following the same procedure as above but without PMCD, the amount of 25-hydroxyvitamin D3 obtained was 350 μg/ml (35% of the conversion ratio from the material).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[C:13]12([NH2:23])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>CN(C=O)C>[C:13]12([NH:23][C:4]3[C:5]4[S:10][CH:9]=[C:8]([CH3:11])[C:6]=4[N:7]=[C:2]([Cl:1])[N:3]=3)[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: Cc1csc2c(NC34CC5CC(CC(C5)C3)C4)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 1.13 g (7.5 mmol) of 1-adamantaneamine was added dropwise to the resulting rid solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 1.10 g (yield: 100%) of the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:18]2([S:22][CH2:21][CH2:20][S:19]2)[CH2:17]1)=[O:15])[CH3:13])=O)C1C=CC=CC=1.C(OCC)C.[BrH:33]>C(O)(=O)C>[BrH:33].[NH2:11][C@H:12]([C:14]([N:16]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][C:18]2([S:22][CH2:21][CH2:20][S:19]2)[CH2:17]1)=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[C@H](N)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 1.4 g of 7-[N-benzyloxycarbonyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid in 20 ml of 20% hydrobromic acid in glacial acetic acid and stir the mixture at room temperature for 2 hours. Add the mixture dropwise to diethyl ether at 0°-5° C. to give 7-[(S)-alanyl]- 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid hydrobromide which is used immediately in the process described in paragraph F below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([NH2:7])=[O:6].CO[C:15]([N:19]([CH3:21])[CH3:20])(OC)[CH3:16]>>[CH3:20][N:19]([CH3:21])/[C:15](=[N:7]/[C:5](=[O:6])[C:4]1[CH:8]=[C:9]([I:12])[C:10]([CH3:11])=[C:2]([F:1])[CH:3]=1)/[CH3:16]
Reactant: Cc1c(F)cc(C(N)=O)cc1I
Reactant: COC(C)(OC)N(C)C
Product: C/C(=N\C(=O)c1cc(F)c(C)c(I)c1)N(C)C
Temperature: 120 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 3-fluoro-5-iodo-4-methylbenzamide (preparation 50b) and (1,1-dimethoxyethyl)dimethylamine was heated at 120° C. in a sealed tube. After 2 hours, the reaction mixture was cooled and the solvent was evaporated under reduced pressure to give the title compound (1.84 g, 100%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1ccccc1-c1ccc(CBr)cc1
Yield: 61.3 %

Procedure:
A mixture of 4′-methyl-2-chloro-biphenyl (1.08 g, 5.33 mmol), NBS (1.14 g, 6.40 mmol) and AIBN (175 mg, 1.06 mmol) in CCl4 (37 mL) was heated at reflux for 3 h. The reaction mixture was diluted with CH2Cl2 and the organic solution was washed sequentially with aqueous saturated NaHCO3 (2×), water (1×), and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes to 5% EtOAc-hexanes) to afford the title compound (920 mg). 1H NMR (CDCl3 400 MHz) δ 7.63-7.25 (m, 8H), 4.56 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[CH:15][CH:14]=1
Reactant: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccnc(Br)c3)sc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccnc(N4CCOCC4)c3)sc12
Temperature: 140 °C
Yield: 49.7 %

Procedure:
A stirred suspension of 200 mg (0.44 mmol) 2-bromo-N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-isonicotinamide, 0.38 ml (4.43 mmol) morpholine and 289 mg (0.89 mmol) cesium carbonate in 5 ml N-methylpyrrolidone in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) followed by trituration in ether afforded 100 mg (49%) N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-2-morpholin-4-yl-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 458 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([OH:23])=O)[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1)[NH2:25].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:25][NH:24][C:26]2[N:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][N:27]=2)=[O:23])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1nccc(C(F)(F)F)n1
Reactant: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a mixture of 1-[(benzyloxy-formyl-amino)-methyl]-4,4-dimethyl-cyclohexanecarboxylic acid (0.10 g, 0.31 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.067 g, 0.37 mmol), NMM (0.095 g, 0.93 mmol) and HOAt (0.05 g, 0.37 mmol) in DMF (1 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.11 g, 74%). MH+480.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]2[C:27]3[C:47](=[O:48])[NH:46][CH:45]=[CH:44][C:28]=3[N:29]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)[N:31]=2)[CH:20]=1)C(=O)[O-])(C)C>ClCCl>[NH2:36][CH2:35][CH2:34][CH2:33][NH:32][C:30]1[N:31]=[C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][CH2:17][CH2:16][NH2:12])[CH:20]=2)[C:27]2[C:47](=[O:48])[NH:46][CH:45]=[CH:44][C:28]=2[N:29]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Nc2cccc(CCCN(C(=O)[O-])C(C)(C)C)c2)c2c(=O)[nH]ccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1nc(Nc2cccc(CCCN)c2)c2c(=O)[nH]ccc2n1
Reaction time: 0.5 h

Procedure:
To a premixed solution of TFA (0.5 mL, 6.49 mmol) and dichloromethane (0.5 mL) was added to 1,1-dimethylethyl(3-{3-[(2-{[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-4-yl)amino]phenyl}propyl)carbamate (39 mg, 0.069 mmol) and the mixture was stirred for 30 min. It was then concentrated and the product was lyophilized (30 mg, white solid).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C([C@@H]1[C@H](N)C2[CH:30]=[CH:31][S:32]C=2CC1)CC>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[CH:30]=[CH:31][S:32][C:19]=3[CH2:18][CH2:17][C@@H:16]2[CH2:15][CH2:14][CH3:13])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCC[C@H]1CCc2sccc2[C@H]1N
Product: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.65, 7.05, 6.92, 5.68, 4.31, 2.97-2.80, 2.68, 2.53, 2.05, 1.97, 1.71, 1.51-1.25, 0.86; HRMS (FAB) calcd for C19H27N3S+H 330.2004, found 330.2001. Anal. Calcd for C19H27N3S: C, 69.26; H, 8.26; N, 12.75; S, 9.73. Found: C, 69.21; H, 8.28; N, 12.35.
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([OH:9])=O)[CH2:2][CH3:3].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>O1CCCC1>[CH:23]1([NH:26][C:7]([C@@H:5]2[C@@H:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:25][CH2:24]1
Reactant: CCC[C@H]1O[C@@H]1C(=O)O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC[C@H]1O[C@@H]1C(=O)NC1CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
(2S,3R)-3-Propyl-2-oxiranecarboxylic acid (118 mg, 0.8 mmol), triethylamine (0.8 mmol) and tetrahydrofuran (2 ml) were mixed, and the mixture was cooled to −20° C. A tetrahydrofuran solution (1 ml) of ethoxycarbonyl chloride (86 mg, 0.8 mmol) was gradually added, and the mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran solution (1 ml) of cyclopropylamine (48 mg, 0.8 mmol) was gradually added dropwise, and the mixture was stirred at the same temperature for 2 hours and at room temperature for 2 hours. After the reaction was quenched with water (10 ml), ethyl acetate (10 ml) was added and the solvent was evaporated away under reduced pressure. The mixture was extracted with ethyl acetate (10 ml), and washed with water (5 ml). The solvent was evaporated away under reduced pressure to obtain the title compound as a colorless oil (0.10 g, yield: 76%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:30]3[CH:29]=[N:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Reaction time: 8 h

Procedure:
1-Methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for preparation see Intermediate 1) (185 mg), 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (for a preparation see Journal of Heterocyclic Chemistry, 41(6), 931-939; 2004) (151 mg), potassium carbonate (90 mg) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg) were combined in ethanol and toluene under nitrogen and heated to 80° C. for 18 h. The reaction was concentrated, the residue partioned between ethyl acetate (10 ml) and water (10 ml) and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organics were washed with brine (25 ml), dried with sodium sulphate, filtered and concentrated. The residue was purified by MDAP (formate ×2) and the collected product dissolved in 1,4-dioxane (0.5 ml) and cooled in a CO2 bath then left on a freeze dryer overnight. The resulting white solid was dried at 40° C. under vacuum overnight to give 1-methylethyl ((2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (84.7 mg). LCMS (formate), Rt 0.84 min, MH+ 415
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:12]=[N:13][C:14](=O)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)C>C(O)(=O)C>[C:1]1([N:7]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:13][CH:12]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=NC(=O)c1ccncc1
Solvent: CC(=O)O
Product: c1ccc(-n2ncnc2-c2ccncc2)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6.9 g. of phenylhydrazine in 100 ml. of acetic acid is added 10.0 g. of N-(dimethylaminomethylene)-isonicotinamide. The reaction mixture is stirred at 90° C. for 1.5 hours and then evaporated in vacuo to an organce oil. This oil is dissolved in 250 ml. of chloroform, washed with 60 ml. of saturated sodium bicarbonate solution, then with 60 ml. of water, dried over sodium sulfate and filtered. The chloroform is removed and the residue is dissolved in 60 ml. of ether. Cooling produces 8.8 g. of the desired product as tan crystals, mp. 92°-94° C.
Reaction SMILES: C([N:4]1[C:10]2[CH:11]=[C:12]3[C:17]4([CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[CH2:16][O:15][C:13]3=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)C.Cl>>[CH3:23][N:20]1[CH2:19][CH2:18][C:17]2([C:12]3=[CH:11][C:10]4[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]=4[CH:14]=[C:13]3[O:15][CH2:16]2)[CH2:22][CH2:21]1
Reactant: CC(=O)N1CCCCc2cc3c(cc21)C1(CCN(C)CC1)CO3
Agent: Cl
Product: CN1CCC2(CC1)COc1cc3c(cc12)NCCCC3
Yield: 90.9 %

Procedure:
5-Acetyl-3,5,6,7,8,9-hexahydro-1'-methylspiro [2H-furo[2,3-h]benzazepine-3,4'-piperidine] (D27, 0.25 g, 0.82 mmol) was stirred at reflux under Ar in c. HCl (15 ml) for 4 days. It was then evaporated to dryness, dissolved in dichloromethane, washed with K2CO3 solution, dried (Na2SO4) and evaporated to give the title compound (0.203 g) as a brown gum, still containing ca. 15% of amide (NMR). Chromatography on silica, eluting with 0-15% methanol in dichloromethane, give purer material (0.107 g, 49%)