Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[C:20]2[N:21]=[CH:22][N:23]=[C:24]([S:25][CH3:26])[C:19]=2[S:18][CH:17]=1)=[O:15].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[C:20]2[N:21]=[CH:22][N:23]=[C:24]([S:25]([CH3:26])=[O:35])[C:19]=2[S:18][CH:17]=1)=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(C)c(NC(=O)c2csc3c(SC)ncnc23)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)c(NC(=O)c2csc3c(S(C)=O)ncnc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-methyl-3-(4-(methylthio)thieno[3,2-d]pyrimidine-7-carboxamido)benzoate (500 mg, 1.29 mmol) was dissolved in DCM (6 mL) and m-CPBA (290 mg, 1.67 mmol) was added thereto at 0° C. The reaction mixture was stirred at room temperature for 2 hours, diluted with DCM (30 mL) and washed with sat. NaHCO3 solution. The organic layer was dried with anhydrous MgSO4, filtered with Celite and concentrated to obtain the title compound without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:28][NH:29][C:43]([CH:39]3[CH2:42][CH2:41][CH2:40]3)=[O:44])=[O:27])=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(c3ccc(C(=O)NN)cc3)CCN(Cc3ccccc3)CC2)c1
Reactant: O=C(Cl)C1CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C2(c3ccc(C(=O)NNC(=O)C4CCC4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazide (0.7 g, 1.69 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (0.35 mL, 2.5 mmol) was catalytic DMAP (20 mg) and cyclobutane carbonyl chloride (0.19 mL, 1.69 mmol). The mixture was stirred at 0° C. for 1 hour and at room temperature for 5 hours. The solution was washed with brine (5 mL), dried (MgSO4) and concentrated. Purification by flash chromatography with hexanes/EtOAc (6:4) afforded 0.63 g (75% yield) of cyclobutanecarboxylic acid N′-{4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoyl}-hydrazide. 1HNMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.67 (d, 2H), 7.41-7.08 (comp, 8H), 6.82-6.61 (comp, 3H), 3.79 (s, 3H), 2.41 (s, 2H), 3.09-3.02 (m, 1H), 2.41-2.23 (comp, 8H), 2.19-1.67 (comp, 6H); MS (M+1) 498.2.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1.O>CO>[CH:3]1([CH2:8][CH2:9][CH2:10][CH:11]([OH:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)CCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)CCCC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
NaBH4 (3.15 g; 83 mmol) was added portionwise to a solution of 5-cyclopentylpentan-2-one (16.0 g; 104 mmol) in MeOH (125 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. Water (100 ml) was added cautiously and the mixture extracted with MTBE (3×250 ml). The organic phases were combined, washed with brine (3×50 ml), dried over MgSO4, concentrated in vacuo and distilled (52° C.-56° C./0.045 torr) to give 14.5 g (90% yield) of 5-cyclopentylpentan-2-ol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2C([C:51]([O:53][CH:54]([CH3:65])[C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)=[O:52])N)=CC=CC=1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:51]([O:53][CH:54]([CH3:65])[C:55]2[CH:56]=[CH:57][C:58]([C:61]([F:62])([F:64])[F:63])=[CH:59][CH:60]=2)=[O:52])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Reactant: CC(OC(=O)C(N)c1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)c1ccc(C(F)(F)F)cc1
Product: CC(OC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)c1ccc(C(F)(F)F)cc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and α-methyl-4-trifluoromethyl)benzyl N-succinimidocarbonate (precursor 4c), according to the general working procedure 170 mg of 2′-(α-methyl-4-(trifluoromethyl)benzyloxycarbonyl-aminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained as a racemate. MS (ES+): m/e=548 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17].[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28])(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:25]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: FC(F)(F)CNc1cnccc1-c1ccccc1Cl
Product: CS(=O)(=O)c1cc(C(=O)N(CC(F)(F)F)c2cnccc2-c2ccccc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(2-chlorophenyl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Further purification by preparative HPLC (Gemini NX) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless solid (31%). MS (ESI): m/z=537.045 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:8][CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=3)[N:12]=[C:11]2[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:7][CH2:6][CH2:5]1.Cl[C:30]1[N:35]=[CH:34][N:33]=[C:32]([NH2:36])[C:31]=1[CH:37]1[CH2:39][CH2:38]1>>[N:4]1([CH2:8][CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=3)[N:12]=[C:11]2[CH:23]2[CH2:24][CH2:25][N:26]([C:30]3[N:35]=[CH:34][N:33]=[C:32]([NH2:36])[C:31]=3[CH:37]3[CH2:39][CH2:38]3)[CH2:27][CH2:28]2)[CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ncnc(Cl)c1C1CC1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Agent: Cl
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C4CC4)CC3)n2)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine trihydrochloride and 6-chloro-5-cyclopropyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=476, obsd=476). 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.66-7.56 (m, 1H), 7.55-7.49 (m, 1H), 7.47 (s, 1H), 7.07 (t, J=9.1 Hz, 1H), 6.16 (s, 2H), 4.19 (d, J=13.0 Hz, 2H), 3.88 (t, J=6.3 Hz, 2H), 3.11 (t, J=6.9 Hz, 4H), 3.05-2.86 (m, 3H), 2.69 (t, J=6.2 Hz, 2H), 2.26 (s, 3H), 1.92 (ddt, J=26.3, 10.1, 5.7 Hz, 6H), 1.49 (q, J=6.9 Hz, 1H), 1.09-0.95 (m, 2H), 0.43 (d, J=5.2 Hz, 2H).
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[Br:38][C:39]1[C:48]([O:49][C@H:50]2[CH2:55][CH2:54][C@H:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:52][CH2:51]2)=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][C:43]([C@:60]1([CH3:66])[CH2:64][O:63]C(=O)[NH:61]1)=[CH:44]2>>[NH2:61][C@@:60]([C:43]1[CH:42]=[CH:41][C:40]2[C:45](=[CH:46][CH:47]=[C:48]([O:49][C@H:50]3[CH2:51][CH2:52][C@H:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:54][CH2:55]3)[C:39]=2[Br:38])[CH:44]=1)([CH3:66])[CH2:64][OH:63]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2Br)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2Br)CC1

Procedure:
(R)-2-amino-2-(5-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 31% yield using (R)-4-(5-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=419.29 [M−NH2]+. 1H NMR (MeOD) δ: 8.29 (d, J=9.0 Hz, 1H), 7.92-7.96 (m, 2H), 7.69 (dd, J=9.0, 2.0 Hz, 1H), 7.50 (d, J=9.3 Hz, 1H), 4.37-4.47 (m, 1H), 3.96 (d, J=11.5 Hz, 1H), 3.85 (d, J=11.5 Hz, 1H), 2.20-2.29 (m, 2H), 1.90-1.97 (m, 2H), 1.78-1.83 (m, 3H), 1.50-1.63 (m, 2H), 1.10-1.30 (m, 3H), 0.94 (s, 9H)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[C:25]1([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1>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.COCCOC>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 100 °C
Yield: 34.6 %

Procedure:
Ethyl 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (2.6 g, 5.76 mmol), phenyltributylstannane (2.24 mg, 6.10 mmol), tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.02 mmol), toluene (15 ml) and anhydrous DME (1.5 ml) were placed in a Schlenk vessel equipped with a magnetic stirring bar. The vessel was purged with argon, sealed and heated at 100° C. overnight. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (0.8 g, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25]C)C(O)=O)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[C:18]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(C(=O)O)cc1C(C)(C)C
Reactant: COc1ccc(N)c(OC)c1
Product: CC(C)(C)c1cc(-c2nc3ccc(O)cc3o2)ccc1O

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3-tert-butyl-4-methoxybenzoic acid and was obtained as a white solid, m.p. 220–222° C.; MS m/e 284 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:12](OCC)=[O:13].[Na]>CCCCCC.C(O)C>[CH:12]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]#[N:11])=[O:13]
Reactant: N#CCc1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCC
Solvent: CCO
Product: N#CC(C=O)c1ccccc1

Procedure:
A 20.0 g. amount of sodium hydride (50% in oil) is added portionwise with stirring to a solution of 20.0 g. of phenylacetonitrile and 40.0 ml. of ethyl formate in 200 ml. of sodium dried benzene. The mixture is heated on a steam bath to start the reaction and after the vigorous reaction has subsided, the mixture is heated on the steam bath for 2 hours with stirring. Ethanol is then added dropwise to decompose the excess sodium hydride. The mixture is then swamped with n-hexane and the precipitate is collected and washed with n-hexane. The precipitate is suspended in water then an excess of dilute hydrochloric acid is added and the product is extracted with ether. The ether extracts are dried and evaporated. The residue is crystallized from acetone-n-hexane to give 12.0 g. of the product of the Example m.p. 161°-163° C. Reference: D. J. Brown and T. C. Lee, J. Chem. Soc. (C), 214 (1970).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].ClC1C2C(=CC3C=C(OC)C(OCCCl)=CC=3C=2)N=CC=1C#N.Cl.N1C=CC=CC=1.[Cl:54][C:55]1[C:61]([O:62][CH3:63])=[CH:60][C:58]([NH2:59])=[C:57]([CH3:64])[CH:56]=1.C(OCCO)C>>[Cl:54][C:55]1[C:61]([O:62][CH3:63])=[CH:60][C:58]([NH:59][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:22]#[N:23])=[C:57]([CH3:64])[CH:56]=1
Reactant: COc1cc(N)c(C)cc1Cl
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCCl
Agent: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OCCCl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(C)cc1Cl
Temperature: 135 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A mixture of 248 mg (0.714 mmol) of 4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 10 mg of pyridine hydrochloride, 150 mg (0.874 mmol) of 4-chloro-5-methoxy-2-methylaniline and 5 mL of 2-ethoxyethanol is stirred and heated to 135° C. After 1 hour, the reaction is cooled to room temperature, quenched with 0.2 mL of triethylamine and concentrated in vacuo. The residue is dissolved in 1:1 hexane/ethyl acetate with a little dichloromethane and chromatographed on silica gel eluting with 1:1 hexane/ethyl acetate, then ethyl acetate to provide 0.282 g of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture) as a dull yellow solid (81%), m.p. 132–68° C. dec.
Reaction SMILES: ClC1C(C[N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=NC=CN=1.[NH2:20]N.CO>C(Cl)Cl>[C:10]1(=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[NH:9][NH:20]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nccnc1Cl
Reactant: NN
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH][nH]c(=O)c2ccccc12
Reaction time: 2.5 h

Procedure:
A solution of 2-(3-chloropyrazin-2-ylmethyl)-isoindole-1,3-dione (10.0 g, 36.5 mmol) in anhydrous CH2Cl2 (200 mL) was charged with hydrazine (2.87 mL, 2.93 g, 91.3 mmol, 2.5 eq.) at rt, under N2 atmosphere. After 2.5 h, MeOH (30 mL) was added and the reaction was heated until the solution was homogenous. The reaction mixture was allowed to stir for 19 h. The white ppt that had formed (2,3-dihydrophthalazine-1,4-dione byproduct), was filtered off and washed several times with ether. The clear filtrate was concentrated in vacuo and the concentrate was dissolved in EtOAc and filtered again to remove white ppt. All solvent was removed, giving a yellow oil, which was dissolved into EtOAc and ether and charged with HCl (g). The title compound, a pale yellow solid, instantly precipitated. The title compound was dried in a 40° C. oven for 72 h, affording the title compound, as a dark yellow solid; 1H NMR (400 MHz, CD3OD) δ 4.55 (2 H, s), 8.27 (1 H, d, J=2.52 Hz), 8.54 (1 H, d, J=2.56 Hz); MS (ES+): #m/z 143.96/145.96 (100/60) [MH+]; HPLC: tR=0.41 min (OpenLynx, polar—7 min).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1N
Reaction time: 0.25 h

Procedure:
To a solution of 3-amino4-carbethoxypyrazole (15 g, 96.7 mmol) in acetonitrile (750 mL) was add NaH (60% oil dispersion, 4 g, 100 mmol) at rt. After 15 min., 4-methoxybenzyl chloride (15.7 g, 100 mmol) was added with stirring. The reaction was allowed to run for 24 h. The reaction mixture was then diluted with EtOAc and washed with H2O, brine and dried (Na2SO4). Removal of the solvent gave the crude product which was further purified by flash column (silica gel, EtOAc/hexane, 1:1) to give ethyl 5-amino-2-p-methoxybenzyl-4-pyrazolecarboxylate (4.2 g, LC: 3.10′ MH+: 276) along with Ethyl 5-amino-1-p-methoxybenzyl-4-pyrazolecarboxylate (4.5 g) (LC: 3.07′ [Gradient 1] MH+: 276) and mixture of the two (10.2 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3Br)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[NH4+:17]>C1COCC1.C(OCC)(=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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3[C:8]3[CH:9]=[CH:4][CH:5]=[CH:6][N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Brc1ncoc1-c1ccc2c(c1)OCO2
Reactant: [NH4+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(-c2ncoc2-c2ccc3c(c2)OCO3)nc1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a degassed solution of 5-benzo[1,3]dioxol-5-yl-4-bromo-oxazole (50 mg, 0.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.009 mmol, 0.05 equiv) in THF (2 mL) was added 2-zinc bromo -pyridine (1 mL, 0.5 M in THF, 0.500 mmol, 2.6 equiv). The resulting reaction mixture was heated to reflux overnight, cooled to ambient temperature, treated with saturated aqueous ammonium chloride, and diluted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography (50% ethyl acetate in hexane) provided 2-(5-Benzo[1,3]dioxol-5-yl-oxazol4-yl)-pyridine (22.7 mg, 46%). [LCMS: Rt=1.79 min, M+H=267.1]
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1.[Br:26]N1C(=O)CCC1=O>C(#N)C(C)C>[Br:26][CH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(C#N)cc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)C#N
Product: N#Cc1ccc2ccc(CBr)cc2c1
Temperature: 80 °C
Yield: 58.2 %

Procedure:
2,2′-azobisisobutyronitrile (491 mg, 3 mmol) and isobutyronitrile (50 ml) were added to 7-methyl-2-naphthalene carbonitrile (5.0 g, 30 mmol) at room temperature. N-bromosuccinimide (5.3 g, 30 mmol) was added thereto, and the mixture was heated at an internal temperature of 80° C. for 2 hours. After that, the experiment was conducted in the same way as Example 12. Analysis by reversed-phase chromatography, by use of the obtained product from Example 11 as a standard sample revealed that 4.3 g of the title compound was obtained (58% yield).
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O>[Br:1][C:2]1[C:9]([O:10][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCCCCBr
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1c(OC)ccc(C=O)c1Br
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (225.2 g, 975 mmol) and DMF (660 ml) were mixed, and potassium carbonate (148.2 g, 1.07 mol) and bromopentane (133 ml, 1.07 mol) were successively added to this solution. The mixture was stirred at 90° C. for 1.5 hours and cooled to room temperature. Water (800 ml) was added to stop the reaction. The aqueous layer was extracted successively with diethyl ether (1000 ml, 500 ml) and ethyl acetate (500 ml). The organic layers were combined, washed successively with water (200 ml) and saturated brine (200 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 2-bromo4-methoxy-3-pentyloxybenzaldehyde.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CC#N>[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCCNCc1nc2ccccc2[nH]1
Yield: 43.6 %

Procedure:
2-Chloromethylbenzimidazole (19.81 g, 118.9 mmol) was added as a solid to a mechanically stirred and cooled (1.2° C. internal temperature) solution of (4-amino-butyl)-carbamic acid tert-butyl ester (56.0 g, 297.3 mmol) and DIPEA (51.8 mL, 297.3 mmol) in CH3CN (3 L) under N2. After 4.5 h at low temperature the cooling bath was removed and the mixture was concentrated in vacuo. The residue was taken up in CH2Cl2 (1.5 L) and washed with brine (1 L). The aqueous layer was extracted with CH2Cl2 (2×500 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford a yellow foamy solid. Purification by column chromatography on silica gel (CH2C2/MeOH/NH4OH (98:1:1) to CH2Cl2/MeOH/NH4OH (80:10:10)) afforded product containing mixed fractions. Repurification of these fractions by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH (98:3:3)) afforded the title compound as a yellow solid (16.5 g, 44%). 1H NMR (CDCl3) δ 1.50 (s, 9H), 1.60-1.64 (m, 4H), 2.70-2.74 (m, 2H), 3.10-3.18 (m, 2H), 4.13 (s, 2H), 4.86 (s, 1H), 7.19-7.25 (m, 2H), 7.50-7.95 (m, 2H), 10.4 (bs, 1H); 13C NMR (CDCl3) δ 26.1, 27.3, 28.1, 39.7, 41.2, 47.2, 47.7, 48.3, 49.4, 78.9, 121.7, 153.9, 155.9; ES-MS m/z 319 (M+H). Anal Calcd. For C17H26N4O2.0.2(H2O): C, 63.41; H, 8.26; N, 17.40. Found: C, 63.51; H, 8.19; N, 17.33.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:11][C:12]1[C:13]([OH:18])=[CH:14][C:15]2[C:2]([CH3:10])([CH3:3])[CH2:4][CH2:5][C:6]([CH3:8])([CH3:7])[C:16]=2[CH:17]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Cc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
50.8 g (0.27 mol) of 2,5-dichloro-2,5-dimethylhexane, 30 g (0.27 mol) of 2-methylphenol and 500 ml of dichloromethane are introduced into a three-necked flask. 14.8 g (0.11 mol) of aluminium chloride are added portionwise, at 0° C., and the mixture is stirred at room temperature for twelve hours. The reaction medium is poured into ice-cold water, the mixture is extracted with dichloromethane and the organic phase is separated out after settling has taken place, washed with bicarbonate solution, dried over magnesium sulphate and evaporated. The residue obtained is triturated in hexane and filtered off and, after drying, 54.4 g (90%) of the expected phenol, with a melting point of 125-6° C., are collected.