Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]([NH:12][C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]2)=O)[CH2:10][OH:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:24][C:13]([CH:15]3[CH2:16][CH2:17][N:18]([CH2:21][C:22]#[N:23])[CH2:19][CH2:20]3)=[N:12][C:9]=2[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: N#CCN1CCC(C(=O)NC(CO)C(=O)c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: N#CCN1CCC(c2nc(CO)c(-c3ccc(F)cc3)o2)CC1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
In a 5-l round bottom flask combine 1-cyanomethyl-piperidine-4-carboxylic acid-[2-(4-fluorophenyl)-1-hydroxymethyl-2-oxoethyl] amide (100 g, 0.296 mole) and acetonitrile (1.4 l) and cool to -15° C. To the solution is added trifluoroacetic acid (22.8 mL, 0.296 mole) at such a rate as to maintain a temperature below -10° C. The resulting suspension is stirred at -10° C. to -15° C. for 10 minutes, then trifluoroacetic anhydride (125.6 mL, 0.890 mole) is charged at such a rate as to maintain a temperature below -10° C. After the addition is complete, a solution of pyridine (96.0 mL, 1.19 mole) in acetonitrile (50 mL) is added over 30 minutes maintaining a temperature of -15° C. The reaction mixture is warmed to room temperature, water (100 mL) is added then the reaction temperature is increased to 40° C. and the solution is stirred for 1.5 hours. The reaction mixture is concentrated to about 250 mL and a 1:1 mixture of saturated aqueous sodium chloride:water (1.5 l) is added. The aqueous suspension is washed with ethyl acetate (4×800 mL) and to the combined organic extracts is added sodium sulfate (100 g) and Dacro brand activated carbon (100 g). After sitting 1 hour, the slurry is filtered through sintered glass and concentrated to an oil. The oil is dissolved in acetonitrile (200 mL) and saturated aqueous sodium bicarbonate (1.2 l) is added in portions to effect crystallization of the free base. The resulting slurry is cooled to 0° C., the solids are collected by filtration and dried to constant weight to give {4-[5-(4-fluorophenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl} acetonitrile (85 g, 0.255 mole) as a monohydrate 1H NMR (400 MHz, CDCl3) d 1.91 (m, 2H), 2.25 (m, 2H), 2.47 (m, 2H), 2.70 (m, 1H), 2.85 (m, 3H), 3.55 (s, 2H), 4.68 (d, 2H), 7.03 (t, 2H), 7.58 (q, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.Cl.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][NH2:26]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:25]([C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])[N:26]=1)=[O:15]
Reactant: NNc1ccc(F)cc1F
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
4-(4-Bromo-phenyl)-2-oxo-3-butenoic acid methyl ester (50.0 g, 185.8 mmol) prepared in Step 2 of Preparation 17 and 2,4-difluorophenylhydrazine hydrochloride (36.9 g, 204.4 mmol) were added to acetic acid (600.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 73.4 g of 5-(4-bromo-phenyl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester as a yellow liquid.
Reaction SMILES: CC(C)=O.CN.[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH2:27]([N:29](CC)CC)C>O>[CH3:27][NH:29][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CN
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)NC
Temperature: 0 °C

Procedure:
To 500 cc of acetone was added 15.5 g of methylamine to form a mixture. 60.0 g of stearoyl chloride was drop-wise added to the mixture, while the mixture was stirred and cooled using ice water. The addition was conducted at a temperature of not higher than 20° C. Further, 20.2 g of triethylamine was dropwise added to the mixture at a temperature of not higher than 20° C. After the addition was complete, the mixture was allowed to react for 3 hours. The reaction mixture was then poured into water and the aqueous mixture was filtered to collect produced crystals, and the crystals were recrystallized from a mixed solvent of ethyl acetate and methanol to give a white crystalline product of N-methylstearic amide (Amide compound No. 1 mentioned above).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH2:9].C([O-])([O-])=O.[Na+].[Na+].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][C:16](=[O:18])[CH3:17]
Reactant: NCc1ccncc1Br
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1ccncc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of (3-bromopyridin-4-yl) methanamine (3.5 g, 19 mmol) in DCM (880 mL) is added Na2CO3 (3.0 g, 28 mmol), then acetyl chloride (1.6 g, 21 mmol) is added at 0° C. under N2 atmosphere. The mixture is stirred at room temperature for 3 hrs and then it is diluted with DCM. The mixture is washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product. Purification by flash column chromatography affords 2.1 g of N-(3-Bromo-pyridin-4-ylmethyl)-acetamide.
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][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[CH:10]=[CH:11][N:12]=1
Reactant: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1

Procedure:
To 4-(4-trifluoromethyl-phenyl)-pyridine 1-oxide (2.4 g, 10 mmol) was added phosphorous oxychloride (12 mL) at room temperature. The reaction mixture was heated at reflux for 5 h. POCl3 was removed under reduced pressure, and the residue was partitioned between EtOAc and aqueous ammonium hydroxide. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on a Biotage 40 M column (8:1 hexanes: EtOAc) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 258.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][C:30](=[O:33])[CH:31]=[CH2:32])[CH:19]=[CH:20][CH:21]=3)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Nc2cc(Nc3cccc(Br)c3)ncn2)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(Nc2cc(Nc3cccc(Br)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of 3-[6-(3-bromophenylamino)-pyrimidin-4-ylamino]phenylamine (250 mg, 0.7 mmol) and triethylamine (180 mg, 1.75 mmol) in 5 mL of THF was stirred at RT. Acryloyl chloride (80 mg, 0.9 mmol) was added into the reaction mixture and it was stirred at RT for 1 h. The solvent was removed by vacuum evaporation and the crude product was purified by flash chromatography on silica gel with EtOAc/DCM solvent system to afford 115 mg (40% yield) of the title compound as a light colored solid. MS (m/z): MH+=410, 412. 1H NMR (DMSO): 10.15 (s, 1H), 9.36 (s, 1H), 9.28 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.51-7.11 (m, 5H), 6.47 (dd, 1H, J1=10.1 Hz, J2=17.0 Hz), 6.27 (dd, 1H, J1=1.9 Hz, J2=17.0 Hz), 6.20 (s, 1H), 5.76 (dd, 1H, J1=10.1 Hz, J2=1.9 Hz) ppm.
Reaction SMILES: C([O:4][CH:5]([CH3:20])[CH:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[N:12]([CH3:19])[CH2:11]2)O)(=O)C.S(=O)(=O)(O)[O-].[K+].C(Cl)Cl.[Cl-].[Na+]>C(=O)(O)[O-].[Na+].O>[O:4]=[C:5]([CH3:20])[CH2:6][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[N:12]([CH3:19])[CH2:11]2
Reactant: CC(=O)OC(C)C(O)c1ccc2c(c1)CN(C)C(=O)N2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Cc1ccc2c(c1)CN(C)C(=O)N2

Procedure:
A mixture of 6-(2-acetoxy-1-hydroxypropyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone (6.47 g) prepared in Step 3 and potassium bisulfate (4.75 g) are ground together and placed under aspirator vacuum in an oil bath at 170° C. until all the material is a melt. Upon cooling the residue is partioned between methylene chloride (100 ml) and water (50 ml). The aqueous is diluted with 50 ml sat. sodium bicarbonate solution and sodium chloride (30 g) and then extracted with methylene chloride. The combined methylene chloride extracts are washed with sat. sodium bicarbonate, sat. aqueous sodium chloride solution, dried over Na2SO4, filtered and evaporated in vacuo. The residue dissolved in 5% methanol in chloroform was purified using flash chromotography on a silica gel column (230-400 mesh) to obtain pure 6-(2-oxopropyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone which was used in the next step.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH:16]([OH:27])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[O:5][CH2:4]1.N1C=CN=C1.[Si:33](Cl)([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.C(Cl)Cl.CCCCCCC>[Si:33]([O:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][C@@H:6]([CH:16]([OH:27])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[O:5][CH2:4]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(O)Cc2ccccc2[N+](=O)[O-])OC[C@H]1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](C(O)Cc2ccccc2[N+](=O)[O-])OC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
A solution of intermediate tert-butyl (2S,5R)-5-(hydroxymethyl)-2-[1-hydroxy-2-(2-nitrophenyl)ethyl]morpholine-4-carboxylate and imidazole (3.2 eq.) in dry DMF (0.43 M) was treated with neat TBDPS-Cl (1.1 eq.) and the final solution stirred at room temperature for 48 h, diluted with DCM and heptane (excess) and concentrated. The residue was purified by automated silicagel flash chromatography system eluted with a gradient 10% to 50% EtOAc in hexanes, to afford title compound as white foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCC(=O)O
Reactant: CCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(=O)NCC(=O)O
Yield: 72.4 %

Procedure:
Glycine (1.5 g, 20 mmol) and heptanoyl chloride (22 mmol) were reacted in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 5. The crude product was recrystallized from EtOAc (30 ml) to give title compound (2.71 g, 72%), m.p. 98°-100° C.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][C:14]2[S:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=2)[S:11][CH:12]=1)=[O:7])C.[OH-].[Na+]>C1COCC1.Cl>[C:19]([C:16]1[S:15][C:14]([CH2:13][C:10]2[S:11][CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1csc(Cc2ccc(C(C)=O)s2)n1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cc2nc(C(=O)O)cs2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(5-acetyl-thiophen-2-ylmethyl)-thiazole-4-carboxylic acid ethyl ester (2.20 g, 7.46 mmol) in THF (32 mL) was treated at rt with 1N NaOH (16 mL, 16.00 mmol) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was poured in 1N HCl and extracted twice with EA. The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a deep brown foam. LC-MS-conditions 02: tR=0.78 min, [M+H]+=268.08.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH:14]([CH3:16])[CH3:15])[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH:14]([C@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][NH:11]1)([CH3:16])[CH3:15]
Reactant: CC(C)[C@H]1CN(Cc2ccccc2)CCN1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)[C@H]1CNCCN1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
(3S)-1-(Benzyl)-3-isopropylpiperazine (358 mg) was dissolved in acetic acid (10 mL), and to the solution 10% palladium on carbon (40 mg) was added, and the mixture was then stirred at 50° C. under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:ammonia-saturated methanol=20:1) to obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[C:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>ClC1C=CC=CC=1>[C:13]1([NH:23][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)=[NH:11])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCc1cccc(NC#N)c1
Reactant: Nc1cccc2ccccc12
Agent: Cl
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Yield: 6.4 %

Procedure:
A solution of m-ethylphenylcyanamide (730 mg, 2.99 mmol) and 1-naphthylamine hydrochloride (900 mg, 5.05 mmol) in chlorobenzene (20 ml) was heated at 140°-145° C. for 12 hours. It was allowed to cool to room temperature, concentrated and the residue was partitioned between dichloromethane and 10% NaOH solution. The organic layer was concentrated and the resulting residue was recrystallized from abs. EtOH-H2O to give N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine (55 mg, 4%) as off-white needles. mp 96°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]#N)=[CH:6]2.[H-].C([Al+]CC(C)C)C(C)C.C[OH:27].Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([CH:14]=[O:27])=[CH:6]2
Reactant: COc1cc2c(cc1OC)CC(C#N)=C2
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)CC(C=O)=C2
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
5,6-Dimethoxy-1H-indene-2-carbonitrile (1.8 g) was suspended in dry toluene (40 ml) under an atmosphere of nitrogen. The reaction mixture was cooled to -5° C. and treated dropwise with a solution of diisobutylaluminium hydride in toluene (1.5M, 13 ml). After 30 minutes the solution was treated with methanol (5 ml) then poured into hydrochloric acid (1M, 200 ml) and stirred for 15 minutes. The resultant solution was extracted into dichloromethane (4×100 ml) then the organic extracts were combined, washed with brine, dried over magnesium sulphate and evaporated to dryness. The residue (1.4 g) was crystallised from dichloromethane:ether to give 5,6-dimethoxy-1-H-indene-2-carboxaldehyde as a white solid, m.p. 125°-128° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:15][CH:16]([OH:18])[CH3:17]>>[Cl:1][C:2]1[N:7]=[C:6]([O:18][CH:16]([CH3:17])[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)O
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4-dichloropyrimidine (5.0 g, 34 mmol) in 2-propanol (84 mL) was added Cs2CO3 (12 g, 37 mmol) and the mixture was stirred at rt for 16 h. The reaction was then heated to 65° C. for 3 h, after which time the reaction was filtered and concentrated. Purification on silica gel using a gradient solvent system of 0-10% EtOAc/Hexanes furnished 2-chloro-4-(propan-2-yloxy)pyrimidine as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J=5.7, 1H), 6.56 (d, J=5.7, 1H), 5.38 (hept, J=6.2, 1H), 1.34 (d, J=6.2, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]([NH:28][NH2:29])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:28][N:29]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(-c3ccccc3)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione was heated in ethanol with benzoic acid hydrazide and the resulting product heated to 250° C. to give 8-chloro-1,6-diphenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine of melting point 193.5°-194.5° C.
Reaction SMILES: [CH3:1][C:2]1([C@H:5]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[O:21][C:22](S(C)=O)=[N:23][N:24]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH3:6])[CH2:4][CH2:3]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CN(C=O)C>[CH3:1][C:2]1([C@H:5]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[O:21][C:22]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[N:23][N:24]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH3:6])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(S(C)=O)o3)cc12)C1(C)CC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(N4CCN(C)CC4)o3)cc12)C1(C)CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
To a solution of 4-((R)-1-(1-methylcyclopropyl)ethylamino)-6-(5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (16.00 mg, 0.041 mmol) in NMP (0.5 mL, 0.082M) was added 1-methylpiperazine (20.63 mg, 0.206 mmol) followed with DIPEA (0.029 mL, 0.165 mmol). The solution was stirred at 130° C. for 30 min in a Biotage Initiator microwave. The reaction mixture was dissolved in 1.5 mL of DMF and directly purified on Reverse Phase HPLC to yield desired product (2.65 mg, 15% yield). 1H NMR (599 MHz), δ 8.33 (s, 1H), 8.27 (s, 1H), 7.20 (s, 1H), 3.96-3.89 (m, 1H), 3.63-3.53 (m, 4H), 2.72-2.23 (m, 7H), 1.37 (d, J=6.4 Hz, 3H), 1.23 (s, 3H), 0.68-0.58 (m, 1H), 0.55-0.49 (m, 1H), 0.39 (m, 2H). MS (ES+) m/z: 424.90 (M+H); HPLC: 97%, retention time: 1.70 min (analytical HPLC Method B).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCCl.O1CCCC1>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH:19]2[CH2:20][CH2:21][N:17]([CH:6]3[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:4][CH2:5]3)[CH2:18]2)=[CH:23]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2c(C3CCNC3)c[nH]c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(N2CCC(c3c[nH]c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and 3-pyrrolidine-3-yl-1H-indole (186 mg, 1 mmole) were dissolved in a mixture of dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml). Glacial acetic acid (57 μl, 1 mmole) and sodium sulfate (500 mg) were added to this mixture. After a reaction time of 15 minutes sodium triacetoxy boron hydride (318 mg, 1.5 mmole) was added to the reaction mixture and stirred for 4 days at RT. The reaction mixture was worked up by distilling off the solvent and adding saturated sodium hydrogen carbonate solution (20 ml) and water (20 ml). This aqueous phase was extracted with DCM (3×30 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The chromatographic purification of the substance mixture was carried out on silica gel with methanol/30% aqueous ammonia (500:1). On dissolving the substance mixture in the solvent a colourless solid precipitated out, which was filtered off. This was identified by NMR spectroscopy as the non-polar diastereoisomer of {4-[3-(1H-indol-3-yl)-pyrrolidine-1-yl]-1-phenylcyclohexyl}-dimethylamine. The non-polar diastereoisomer was obtained in a yield of 79 mg (20%). The remaining substance mixture was purified by flash chromatography. The diastereoisomer mixture was obtained in a yield of 136 mg (35%).
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:3][OH:4]
Reactant: CC(N)(C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(N)(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.5 %

Procedure:
To a stirred, cooled suspension of 2-amino-2-phenyl-propionic acid (488 mg) at r.t. in THF (10 ml) under an argon atmosphere was added portionwise LiAlH4 (244 mg). The ice bath was removed and stirring at r.t. was then continued for 20 h. The mixture was cooled in an ice bath, diluted with 5 ml THF and H2O (0.23 ml), 4 N NaOH (0.23 ml) and H2O (0.92 ml) were added successively and carefully. After 30 min stirring at r.t., the mixture was filtered and the cake was washed with THF. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 2-amino-2-phenyl-propan-1-ol (266 mg) as colorless viscous oil. MS (ISP): 152.3 ([M+H]+)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=1>O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(OC2CCCCO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a mechanically stirred slurry of 10 g of lithium aluminum hydride and 100 mL of tetrahydrofuran was added dropwise with cooling in an ice bath a solution of 32.9 g (0.139 mol) of methyl 4-tetrahydropyranyloxybenzoate at a rate such that the temperature did not exceed 30° C. After stirring 18 hr at room temperature, the solution was treated cautiously with 100 mL of water. The mixture was filtered, and the filtrate was stirred with 200 mL of aqueous sodium hydroxide for 2 hr. The organic layer was separated and evaporated with a rotary evaporator. The residue was dissolved in 200 mL of ether and washed three times with 5% aqueous sodium bicarbonate and dried over sodium sulfate. Evaporation gave 20.58 g of 4-tetrahydropyranyloxybenzyl alcohol as a liquid. 1H NMR (360 MHz, THF-d8): 1.45-2.0 (m's, 6H, CH2), 3.5 (m, 1H, OCH2), 3.8 (m, 1H, OCH2 ), 4.25 (t, J=6, 1H, OH), 4.45 (d, J=6, 2H, ArCH2OH), 5.35 (t, J=3, 1H, OCHO), 6.95 (d, J=8, 2H, ArH), 7.19 (d, J=8, 2H, ArH).