Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([CH2:17][CH3:18])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl.[CH3:22][O:23][NH:24][CH3:25].Cl.C(NCC)(C)C>CO.C(OCC)(=O)C.[Cl-].[Na+].O.CN(C=O)C>[CH3:22][O:23][N:24]([CH3:25])[C:4]([C:6]1[N:7]([CH2:17][CH3:18])[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CNOC
Reactant: CCOC(=O)c1cc(-c2ccccc2)nn1CC
Agent: CCNC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccccc2)cc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a room temperature solution of the above-prepared 2-ethyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (165 mg, 675 μmoles) in MeOH (2 mL) was added aqueous NaOH (215 μL of a 10 N solution, 215 μmoles) under a nitrogen atmosphere. The resulting mixture was allowed to stir at room temperature overnight. The reaction was acidified with 6 N HCl, diluted with ethyl acetate and brine, and the phases were separated. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude acid was suspended in THF (2 mL), and carbonyldiimidazole was added (140 mg, 860 μmoles), and the mixture was stirred overnight at room temperature. The resulting acylimidazolide was treated with a preformed mixture of MeON(H)Me.HCl (140 mg, 1.43 mmole) and isopropylethylamine (250 μL, 1.43 mmoles) in DMF (1 mL) and the resulting mixture heated to 90° C. overnight. The reaction was then cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with 1 M NaHSO4 (3×), brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound (130 mg, 74% yield) as a thick oil.
Reaction SMILES: [N+](C(CC)C)([O-])=O.[N+](C(CCC)C)([O-])=O.[CH3:16][C:17]([N+:31]([O-])=O)([CH2:28][CH2:29][CH3:30])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>>[CH3:16][C:17]([NH2:31])([CH2:28][CH2:29][CH3:30])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1
Reactant: CCCC(C)(Cc1c[nH]c2ccccc12)[N+](=O)[O-]
Agent: CCC(C)[N+](=O)[O-]
Agent: CCCC(C)[N+](=O)[O-]
Product: CCCC(C)(N)Cc1c[nH]c2ccccc12

Procedure:
If the 2-nitrobutane in Example 1 is replaced by the corresponding quantity of 2-nitropentane, using the same procedure as in Example 1, the intermediate product obtained is 3-(2'-methyl-2'-nitropentyl)-indole; melting point 78°-80°C (from petroleum ether). Reduction yielded 3-(2'-methyl-2'-aminopentyl)-indole, which after recrystallisation from petroleum ether yields needle-shaped crystals of a melting point of 73.5° to 74.5°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+].Br[C:48]1[CH:49]=[C:50]2[C:59](=[C:60]3[C:65]=1[CH:64]=[CH:63][CH:62]=[N:61]3)[NH:58][S:57](=[O:67])(=[O:66])[C:56]1[C:51]2=[CH:52][CH:53]=[CH:54][CH:55]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:1]1([C:48]2[CH:49]=[C:50]3[C:59](=[C:60]4[C:65]=2[CH:64]=[CH:63][CH:62]=[N:61]4)[NH:58][S:57](=[O:67])(=[O:66])[C:56]2[C:51]3=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)Nc2c(cc(Br)c3cccnc23)-c2ccccc21
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: O=S1(=O)Nc2c(cc(N3CCCCC3)c3cccnc23)-c2ccccc21
Yield: 18.6 %

Procedure:
In a similar fashion using route 58 general procedure 126, piperidine (41 μl, 0.42 mmol), Pd2(dba)3 (3 mg, 3 μmol), X-Phos (7 mg, 14 μmol), NaOtBu (67 mg, 0.69 mmol), 12-bromo-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 545 (100 mg, 0.28 mmol) and toluene (2 ml) gave the title compound (19 mg, 19%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[CH2:27]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](O)([C:42]2[C:50]([OH:51])=[CH:49][C:45]3[O:46][CH2:47][O:48][C:44]=3[CH:43]=2)[C:34]1=[O:53])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:27]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]([C:42]2[C:50]([OH:51])=[CH:49][C:45]3[O:46][CH2:47][O:48][C:44]=3[CH:43]=2)[C:34]1=[O:53])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 1-hexyl-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (98%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.38-7.13 (m, 3H), 6.94 (d, 1H), 6.60 (s, 1H), 6.32 (s, 1H), 5.84 (dd, 2H), 5.02 (s, 1H), 3.74-3.63 (m, 2H), 1.70-1.61 (m, 2H), 1.37-1.19 (m, 6H), 0.83 (t, 3H); MS (ES+) m/z 354.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:5][CH:4]=1>N1C=CC=CC=1.C(OC(=O)CC)(=O)CC>[C:14]1([C:12]2[NH:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:2](=[O:1])[CH2:3][CH3:4])=[CH:8][CH:7]=3)=[C:10]([C:24]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])[N:11]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(CO)cc1
Agent: CCC(=O)OC(=O)CC
Solvent: c1ccncc1
Product: CCC(=O)OCc1ccc(-c2[nH]c(-c3cccc4ccccc34)nc2C(=O)Nc2nccs2)cc1
Yield: 88.4 %

Procedure:
5-(4-Hydroxymethylphenyl)-2-(1-naphthyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (300 mg) obtained in Example 61 was dissolved in pyridine (5 ml) and propionic anhydride (5 ml), and the mixture was left standingfor 12 hr. Thereaction mixture was poured into icewater and extracted with ethyl acetate. The ethyl acetate layer was washed with water and, after drying, concentrated. The obtained residue was recrystallized from ethyl acetate to give 2-(1-naphthyl)-5-(4-propionyloxymethylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (150 mg), melting point 281-283° C.
Reaction SMILES: [C:1]([C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+].O>C(O)CO>[CH2:1]([C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc2ccccc2cn1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: c1ccc(Cc2cc3ccccc3cn2)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
303 mg of 3-benzoyl isoquinoline and 9.75 g of hydrazine hydrate were dissolved in 10 mL of ethylene glycol at room temperature, followed by stirring at 150° C. After 10 minutes, to the reaction liquid was added 3.65 g of pulverized potassium hydroxide, followed by warming to 180° C. and continuously reacting for additional 2 hours. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (diethyl ether:n-hexane=1:1) to obtain 280 mg (yield 95%) of a title compound as a light yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([O:27][CH2:28]Cl)=[O:26].[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]([F:33])([F:34])[O:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([O:27][CH2:28][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:26]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(OCCl)c1cccc(OC(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.40 g of chloromethyl 3-trifluoromethoxybenzoate was added, and the mixture was stirred at 70° C. for 6 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.2 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3-trifluoromethoxybenzoate (present compound (45)).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][C:10]3[CH:11]=[CH:12][N:13]4[C:19]([C:20]5[N:25]=[CH:24][CH:23]=[CH:22][N:21]=5)=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:34]>C(#N)C>[Cl:34][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:15]2[C:14]3=[N:17][N:18]=[C:19]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:13]3[CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=c1[nH]c2ccn3c(-c4ncccn4)nnc3c2cc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Clc1nc2ccn3c(-c4ncccn4)nnc3c2cc1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8(7H)-one (2-4) (1.4 g, 4.1 mmol) and DMF (0.032 mL) in acetonitrile (20 mL) was added POCl3 (2.3 mL, 24.6 mmol). After stirring at 120° C. for overnight, the solvent was removed under reduced pressure, and the residue was diluted with acetonitrile, and added water. The resulting solid was collected by filtration to give 8-chloro-9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine (2-5) as a colorless solid.
Reaction SMILES: Cl.[C:2]12([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[OH:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1>>[C:2]12([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:26][CH2:25][O:24][C:23]4[CH:28]=[CH:29][C:20]([OH:19])=[CH:21][CH:22]=4)[CH2:15][CH2:14]3)[CH2:11][CH:6]3[CH2:5][CH:4]([CH2:10][CH:8]([CH2:7]3)[CH2:9]1)[CH2:3]2
Reactant: C1CC(CC23CC4CC(CC(C4)C2)C3)CCN1
Reactant: Oc1ccc(OCCBr)cc1
Agent: Cl
Product: Oc1ccc(OCCN2CCC(CC34CC5CC(CC(C5)C3)C4)CC2)cc1

Procedure:
b)The title compound was prepared from 4-(1-adamantylmethyl)piperidine hydrochloride (350 mg, 1.30 mmol) and 2-(4-hydroxyphenoxy)ethyl bromide (295 mg, 1.36 mmol) as a beige crystalline solid (387 mg, 81%): mp 178-179° C.; 1H NMR (DMSO-d6) 0.93 (d, J=5.1, 2H), 1.05-1.70 (m, 17H), 1.85-2.07 (m, 5H), 2.56 (t, J=6.0, 2H), 2.72-2.88 (m, 2H), 3.90 (t, J=6.0, 2H), 6.63 (d, J=9.0, 2H), 6.71 (d, J=9.0, 2H), 8.88 (bs, 1H); Anal. calcd for C24H35NO2: C, 78.00; H, 9.55; N, 3.79. Found: C, 78.03; H, 9.44; N, 3.77.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:27]C(OC(C)(C)C)=O)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C@@H:16]([CH2:15][S:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 0.50 g (1.023 mmol) of benzyl(R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-tert-butoxycarbonylaminopropionate in 5 ml of dichloromethane was mixed with the same volume of trifluoroacetic acid and left to stand at RT for 1 h. It was then concentrated and directly reacted further.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CN1C(=O)OC[C@@H]1c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of Example 2A (1 g, 4.25 mmol) in 10 mL of anhydrous THF at −78° C. was treated with 4.68 mL (4.68 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred for 1 h. at about −70° C. before adding MeI (1.59 mL, 25.51 mmol). Upon complete conversion of the azetidinone, the reaction was quenched with saturated aqueous NH4Cl and partitioned between EtOAc and water. The organic layer was washed sequentially with saturated aqueous sodium bisulfite, and saturated aqueous NaCl. The resulting organic layer was dried (MgSO4) and evaporated to afford the title compound (a mixture of diasteromers) as a white solid (1.06 g, 93%); 1H NMR (CDCl3) δ 1.07/1.53 (d/d, J=7.5 Hz, 3H), 3.59/3.74 (s/s, 3H), 3.85/4.48 (q/q, J=7.5 Hz, 1H), 4.10-4.14 (m, 1H), 4.60-4.64/4.65-4.69 (m/m, 1H), 4.88-4.92/4.98-5.02 (m/m, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])(=O)=O)[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][S:8]2)=[CH:6][CH:7]=1
Reactant: CC(C)=CCS(=O)(=O)c1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CCSc2cc(Br)ccc21
Yield: 90.5 %

Procedure:
25.00 g (97.0 mmol) of 1-bromo-3-(3-methylbut-2-enylsulphonyl)benzene, 200 ml of toluene and 27.75 g (146.0 mmol) of para-toluenesulphonic acid are introduced into a three-necked flask. The reaction medium is refluxed for four hours and evaporated to dryness. The residue is taken up in aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with heptane. 22.57 g (90%) of the expected compound are obtained in the form of a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=1.P(Br)(Br)([Br:17])=O.C([O-])(O)=O.[Na+]>C1COCC1>[Br:17][CH2:13][C:9]1[CH:8]=[C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OCc1cccc(-c2ncccn2)c1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCc1cccc(-c2ncccn2)c1
Temperature: 60 °C
Yield: 80.5 %

Procedure:
To a stirred solution of (3-(pyrimidin-2-yl)phenyl)methanol [892502-12-4] (2.48 g, 12.92 mmol) in THF (25 mL), POBr3 (4.81 g, 16.79 mmol) was added and the mixture was heated at 60° C. for 90 min. The mixture was cooled to rt, poured into saturated aqueous NaHCO3 solution and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 5%-40% ethyl acetate/heptane) to yield the title compound (2.59 g, 80%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.92 (d, J=5.0 Hz, 2H), 8.48 (t, J=1.6 Hz, 1H), 8.32 (dt, J=7.7, 1.4 Hz, 1H), 7.58-7.62 (m, 1H), 7.49-7.54 (m, 1H), 7.47 (t, J=4.8 Hz, 1H), 4.82 (s, 2H); LCMS RtA=1.04, [M+H]+=249.2/251.2].
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:12][C:13]1C=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:5].Cl.[NH2:28][C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1Cl.ClC1N=CC(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:12][C:13]1[N:28]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][N:14]=1)=[O:5]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1Cl
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1Cl
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)nc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cn1)c1ccccc1Cl

Procedure:
Prepared according to the procedure for 2-chloro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 69) from N-[(1S,2S)-2-aminocyclopentyl]-2-chlorobenzamide hydrochloride (Intermediate 19; 100 mg, 0.363 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 80 mg, 0.436 mmol) to afford the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH2:8]([O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:19]1[CH2:18][CH2:17][CH:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:21][CH2:20]1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(COC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC(OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
3,4 g (0.033 mol) of ethyl chloroformate are added dropwise to a stirred mixture of 6.83 g (0.03 mol) of 4-benzyloxypiperidine hydrochloride, 7.74 g (0.056 mol) of dry K2CO3, 26 ml of water and 26 ml of chloroform. After stirring for 1 hour, the organic phase is decanted after dilution with 54 ml of chloroform, and washed 3 times with 20 ml of water and dried (MgSO4). Evaporation of the solvent in vacuo gives a liquid, which is distilled in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[C:18]([C:36]([F:39])([F:38])[F:37])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[C:18]([C:36]([F:38])([F:37])[F:39])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)OC(C)(C)C)c4)n3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)O)c4)n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of tert-butyl 3-(2-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoate (I29) (0.048 g, 0.088 mmol) in DCM (3 mL) was added TFA (0.5 mL); the reaction was then stirred for 35 minutes at room temperature before concentrating under reduced pressure. The residue was taken up in toluene (2×10 mL) and concentrated under reduced pressure. The resulting residue was taken up in DCM (3 mL) and TFA (0.5 mL) was added. The resulting solution was stirred at room temperature for 1 hour then the volatiles removed by evaporation under reduced pressure. The residue was taken up in toluene (2×20 mL) and concentrated under reduced pressure to give the title compound (I30) in quantative yield; 1H NMR (400 MHz, d6-Acetone) δ 9.14 (s, 1H), 8.62 (s, 1H), 7.96 (s, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.74 (bs, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.44 (dd, J=7.6, 7.6 Hz, 1H), 7.34 (bd, J=8.0 Hz, 1H), 7.25 (dd, J=8.1, 8.1 Hz, 1H), 6.77 (dd, J=8.1, 1.8 Hz, 1H), 3.60 (m, 4H), 3.47 (m, 4H), 3.20 (m, 4H), 2.94 (s, 3H). LCMS Method C: rt 4.93 min; m/z 486.2 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([CH2:18][Cl:19])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH3:20]>>[ClH:3].[Cl:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([CH2:18][Cl:19])[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH3:20]
Reactant: O=S(Cl)Cl
Agent: Cc1nc2ccc(CCl)cc2n1Cc1ccccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Thionyl chloride (5 ml) is added to 1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole (3.56 g), and the solution is stirred for 20 minutes at room temperature and then for 20 minutes at 80° C. After excess thionyl chloride is removed through evaporation under reduced pressure, the residue is dissolved in chloroform (10 ml), and crystallization is performed by adding hexane. The crystals are separated through filtration, washed in hexane, and dried. Thus, 1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloride (4.07 g) is obtained. 1H-NMR (CDCl3, δ): 3.01 (3H, s), 4.68 (2H, s), 5.61 (2H. s), 6.71 (1H, d, J=7.5 Hz), 7.24-7.29 (1H, m), 7.38 (1H, t, J=7.7 Hz), 7.44 (1H, s), 7.52 (2H, d, J=8.2 Hz), 7.92 (1H, d J=8.4 Hz).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1)=[S:11])=O)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O>>[CH2:1]([NH:5][C:6]1[S:11][C:10]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[N:9][N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCNc1nnc(NCCCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 40 from N-butyl-2-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]aminothioxomethyl]hydrazine carboxamide and phosphorus oxychloride. The analytical values are summarized in Table III.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:14]([O:18]CC1C=CC(C(O)=O)=CC=1)[CH2:15][CH:16]=C>C(O)CC>[CH2:14]([O:18][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH2:15][CH3:16]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCO
Product: CCCOCc1cccc(C(=O)O)c1

Procedure:
The reaction of propanol and 3-Chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 3-propoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (m, 1 arom.H); 7.84 (m, 1 arom.H); 7.53 (m, 1 arom.H); 7.46 (m, 1 arom.H); 4.50 (s, OCH2C6H4—); 3.38 (t, CH3CH2CH2O); 1.54 (m, CH3CH2CH2O); 0.87 (t, CH3CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.25 (—C═O); 139.31; 131.63; 130.77; 128.51; 128.22; 128.01; 71.40; 71.16; 22.43; 10.56.