Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[N:5]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14](=[O:22])(=[O:21])[CH2:13][CH2:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1C=CC=CC=1.O1CCCC1>[N:5]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14](=[O:22])(=[O:21])[CH2:13][CH2:12][C:11]=2[C:1]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Nc1ccccc1
Reactant: O=S1(=O)CCC=C(N2CCCC2)c2ccccc21
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)C1=C(N2CCCC2)c2ccccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 80 ml (contg 0.084 mol of COCl2) of a 12.5% solution of phosgene in benzene and 80 ml of tetrahydrofuran was cooled to -50° and a solution of 22.0 g (0.08 mol) of crude 2,3-dihydro-5-(1-pyrrolidinyl)-1-benzothiepin 1,1-dioxide and 8.8 g of triethylamine in 400 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 3 hours, cooled to -60°, and a solution of 8.0 g (0.088 mol) of aniline and 11 g of triethylamine in 200 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 18 hours, refluxed for 3 hours, and part of the tetrahydrofuran was removed by distillation under reduced pressure. The residue was treated with ice water and extracted with dichloromethane. The organic phase was washed with water, dried over sodium sulfate, and evaporated. The residue was redissolved in dichloromethane and ether was added until the solution became turbid. On standing there was collected 22.4 g of a solid precipitate. This was recrystallized from a mixture of 200 ml of tetrahydrofuran and 300 ml of isopropyl ether to give 15.6 g of product, mp 160°-163° dec. Recrystallization from a mixture of 200 ml of dichloromethane and 1600 ml of ether gave 10.4 g of material mp 167°-169° dec.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[O:25])[NH:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:33]([F:38])([F:37])C(O)=O.[Na].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([O:25][CH:33]([F:38])[F:37])=[N:14][N:15]2[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(OCc3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(OC(F)F)c2ccc(OCc3ccccc3)cc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
Tert-butyl 6-(benzyloxy)-3-oxo-2,3-dihydroindazole-1-carboxylate (342 mg) which can be prepared according to the method described in Reference example 32, etc. and potassium carbonate (2.0887 g; manufactured by Sigma-Aldrich Co.) were suspended in dehydrated DMF (10 mL; manufactured by Kanto Chemical Co., Inc.), added with sodium chlorodifluoroacetic acid (853 mg; manufactured by Tokyo Chemical Industry, Co., Ltd.), and stirred at 80° C. for 12 hours. The reaction solution was added to water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=100:0→87:13) to obtain the title compound (264.7 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:1]([N:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Product: O=C(c1ccccc1)N1CC=CCC1
Reaction time: 1.5 h

Procedure:
Benzoyl chloride (60 mmole) is added to a solution of 38 (60 mmole) in pyridine at 4 C. The mixture is allowed to stir for about 1-2 hrs and then further stirred at room temp for 12 hrs. The reaction mixture is made acidic and then extracted with methylene chloride. Following work-up and flash chromatography affords 39.
Reaction SMILES: N1C=CC=CC=1.[Br:7][CH2:8][C:9](Br)=[O:10].[C:12]1([C:18]([OH:21])([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Br:7][CH2:8][C:9]([O:21][C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:20])[CH3:19])=[O:10]
Reactant: CC(C)(O)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(OC(=O)CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
Pyridine (3.84 mL, 47.7 mmol) followed by bromoacetyl bromide (4.16 mL, 47.7 mmol) was added to a solution of 2-phenylpropan-2-ol (5.00 g, 36.7 mmol) in dichloromethane (100 mL) at 0° C., warmed to r.t. and stirred overnight. The reaction mixture was washed with water (3×100 mL), saturated aqueous sodium bicarbonate (3×100 mL), water (2×100 mL), dried (Na2SO4) and concentrated. The crude residue was purified by silica gel flash column chromatography (neutralized with TEA, heptanes) to afford the title compound (2.8 g (non-optimized), 30%) as a colorless oil. 1H NMR (300 MHz, ((CD3)2CO) δ: 7.44 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.2 Hz, 2H), 7.25 (t, J=7.2 Hz, 1H), 4.01 (s, 2H), 1.78 (s, 6H).
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>O1CCCC1.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][S:3][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([Br:10])[N:12]=1)[CH3:9]
Reactant: BrCc1cccc(Br)n1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CSCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.48 g, 11.96 mmol) was suspended in tetrahydrofuran (52.4 mL) and cooled to 0° C. Ethyl mercaptoacetate (0.48 mg, 3.99 mmol) was added and the solution was stirred for 30 minutes at 0° C. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (1.0 g, 3.99 mmol) was added and the solution was allowed to stir until completion. The reaction mixture was then diluted with water and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCCC1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17](=[O:18])[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A mixture of 7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.27 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) was stirred at 40° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.21 g, 83%).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[O:66]([CH2:73][CH:74]1[O:78][C:77](=[O:79])[N:76]([CH2:80][CH2:81][CH2:82]O)[CH2:75]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1C=CC=CC=1>[O:66]([CH2:73][CH:74]1[O:78][C:77](=[O:79])[N:76]([CH2:80][CH2:81][CH2:82][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:21]3=[O:45])=[CH:46][CH:47]=2)[CH2:75]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: O=C1OC(COc2ccccc2)CN1CCCO
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1OC(COc2ccccc2)CN1CCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Yield: 55.2 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 1.29 g of tributylphosphine, 30 ml of anhydrous benzene, 2.98 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.61 g of azodicarbonyldipiperidine and 1.33 g of 3-(5-phenoxymethyl-2-oxooxazolidin-3-yl)propanol (prepared as described in Preparation 114) were used, to give 2.04 g of the title compound, melting at 70° C. to 73° C.
Reaction SMILES: [Br:1][C:2]1[S:24][C:5]2[N:6]([CH3:23])[C:7](=[O:22])[N:8]([CH2:11][CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:25]>Cl.CO.C(Cl)Cl>[Br:1][C:2]1[S:24][C:5]2[N:6]([CH3:23])[C:7](=[O:22])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:25]
Reactant: Cc1c(Br)sc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1c(Br)sc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.2 %

Procedure:
6-bromo-3-(3-(tert-butyldimethylsilyloxy)propyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione (2.4 g, 4.39 mmol) was dissolved in aq. 6N HCl (15 mL) and MeOH (15 mL). The reaction was stirred at RT for 30 min then diluted with DCM (20 mL) and washed with water (2×20 mL). The organic layer was dried over Na2SO4 and concentrated to give 6-bromo-3-(3-hydroxypropyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.7 g, 95.5% yield) as a white solid. LCMS: MH+ 334 and TR=1.049 min. Used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]#[N:24])=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: N#Cc1ccccc1B(O)O
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccccc1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 32.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.023 g (33%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Cl:8][C:7]1[C:2]([N:10]([CH3:9])[CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CNCCOc1ccccc1
Solvent: CN(C)C=O
Product: CN(CCOc1ccccc1)c1nccnc1Cl
Yield: 71 %

Procedure:
A mixture of 2,3-dichloropyrazine (6.64 g, 44.6mmol) and N-methyl-N-(2-phenoxyethyl)amine* (4.5 g, 29.8 mmol) in DMF (5 mL) was placed in a sealed Pyrex tube and heated in a microwave oven (Labwell MW10) for 1×2 min followed by 2×1 min at 75W. The mixture was concentrated and the resulting oil was purified by column chromatography on silica using hexane/EtOAc (95:5 followed by 93:7) to give 5.56 g (71%) of the title product as a colorless oil. HRMS m/z calcd for C13H14ClN3O (M)+ 263.0825, found 263.0824.
Reaction SMILES: ClC1N2C(=[O:11])NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].I[CH2:28][CH3:29].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][C:45](NCC)([C:47](N)=[O:48])[CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:44][CH:45]([C:47]([O:48][CH2:28][CH3:29])=[O:11])[CH2:46]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=2)=[CH:35][CH:36]=1
Reactant: CCI
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Product: CCOC(=O)C1CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with iodoethane, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.440 min, [M+H]30 =512.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH2:6]([N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:15]([C:26](O)=[O:27])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:5][O:4][N:3]([CH3:2])[C:26]([CH:15]1[CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:17][N:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:27]
Reactant: CNOC
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (0.41 g, 4.2 mmol) and 1.23 g (3.5 mmol) of (3RS,4SR)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid in DMF (20 mL) at RT was added Hunig base (1.79 ml, 10.5 mmol) and HATU (1.468 g, 3.9 mmol) and stirring was continued for one hour. The reaction mixture was diluted with ethyl acetate and washed with aq. ammonium chloride solution three times. The separated organic layer was washed with brine and dried on Na2SO4 and concentrated under vacuo yielding 1.36 g (99%) of the title compound as a light yellow oil. ES-MS m/e: 393.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]([C:9]1[O:10][C:11]2[C:16]([C:17](=[O:26])[C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[C:13]([Cl:27])[CH:12]=2)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[C:35]1([CH3:42])[CH:40]=[CH:39]C(Cl)=[CH:37][CH:36]=1.CC[O:45][CH2:46][CH3:47]>C(Cl)Cl>[CH2:19]([C:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:5]([NH:4][CH2:3][CH2:2][NH:1][C:46](=[O:45])[C:47]1[CH:39]=[CH:40][C:35]([CH3:42])=[CH:36][CH:37]=1)[CH:6]([CH3:7])[CH3:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(NCCN)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Reactant: CCOCC
Reactant: Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCNC(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) solution of 2-[1-(2-amino-ethylamino)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (4.1 g, 11 mmol) and triethylamine (2.2 mL, 17 mmol) in methylene chloride (100 mL) was added a solution of p-toluyl chloride (1.7 g 11 mmol) in methylene chloride (20 mL). The reaction was maintained at 0° C. for 2 hours, at which time it as diluted with ether (250 mL). The resultant solution was washed with 1 N hydrogen chloride (2×200 mL), saturated sodium bicarbonate (200 mL) and brine (150 mL), dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (0→60% ethyl acetate/hexanes) to (give 2.8 g, (50%) of the title compound. MS(ES+) m/z 503 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>CN1CCCC1=O>[CH3:1][N:2]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1ncccn1)[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1

Procedure:
(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was reacted with potassium carbonate (100 mg) and 2-bromopyrimidine (50 mg) in N-methylpyrrolidone (3 ml) at 100° C. for 4 hours. The reaction solution was then partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 491.04 (C27H31ClN6O); MS (ESI): 491 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:27]([N:34]([C:42](=[O:44])[CH3:43])[C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)[CH2:26][C@@H:25]3[CH3:45])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[N:9][C:10]=1[CH3:11])=[O:5])C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:42]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][N:7]3[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[N:9]=[CH:8]3)=[CH:17][CH:18]=2)=[O:23])[C@@H:25]([CH3:45])[CH2:26]1)(=[O:44])[CH3:43]
Reactant: CCOC(=O)c1c(C)ncn1CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCn3cnc(C)c3C(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was dissolved in DMF at room temperature and K2CO3 was added. 3-(3-Bromo-propyl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (prepared from the dibromide and the corresponding imidazole with NaH in THF) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (2% MeOH/95% CH2Cl2 to 10% MeOH/90% CH2Cl2) to afford (2S,4R)-3-[3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester. The ester (0.080 g, 0.12 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 16 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-3-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-5-methyl-3H-imidazole-4-carboxylic acid in 61% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(Cl)Cl.[NH2:18][CH2:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C>O>[Cl:1][C:2]1[C:7]([C:8](=[O:9])[NH:18][CH2:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:6]([O:11][CH3:12])[N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: NCc1ncccn1
Reactant: COc1nc(SC)nc(Cl)c1C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1nc(SC)nc(Cl)c1C(=O)NCc1ncccn1
Reaction time: 0.33 h

Procedure:
To a mixture of whole amount of 4-chloro-5-chloroformyl-6-methoxy-2-methylthiopyrimidine (prepared in the above (4)) and methylene chloride 10 ml is dropped a mixture of 2-aminomethylpyrimidine 930 mg, triethylamine 2.38 ml and methylene chloride 10 ml over a period of 5 minutes on an ice bath, and the mixture is stirred for 20 minutes. The mixture is further stirred at room temperature for 40 minutes. The reaction mixture is diluted with water and the water layer is extracted with methylene chloride. The organic layer is dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:ethyl acetate=1:1) and recrystallized from a mixture of methylene chloride, ethyl acetate and isopropyl ether to give 4-chloro-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder, 1.56 g. mp 176-177° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:19])[CH:16](C)[CH3:17].[CH2:21](N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: CCN(CC)CC
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 14 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), isobutyryl chloride (0.55 mL, 5.2 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-butyramide (0.18 g). Mp 133-135° C.;Anal. Calcd. for C15H17NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.76; H, 7.48; N, 5.41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][CH3:13])[O:11][CH2:10]1.[CH2:14]([OH:17])CC.B(F)(F)F.[CH3:22][CH2:23]OCC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:11][CH2:10][CH2:22][CH3:23])([CH2:12][CH3:13])[CH2:14][OH:17]
Reactant: CCC1(c2ccc(Cl)cc2Cl)CO1
Reactant: CCOCC
Reactant: CCCO
Agent: FB(F)F
Product: CCCOC(CC)(CO)c1ccc(Cl)cc1Cl
Reaction time: 24 h

Procedure:
8.68 g (0.04 mole) of 2-(2,4-dichlorophenyl)-1,2-epoxybutane of 95% purity are dissolved in 12 g (0.2 mole) of n-propanol, and a solution of 5.68 g (0.04 mole) of boron trifluoride-etherate in 12 g (0.2 mole) of n-propanol is added dropwise at 20° C. After 24 hours, the mixture is extracted with chloroform, the solvent is removed on a rotary evaporator and the residue is purified by column chromatography using silica gel. The yield is 5.41 g (48.8%) of a colourless oil. 60 MHz-1H-NMR (DCCl3): δ=7.0-7.6 ppm (m, 3H, aromatic); 3.7-4.4 ppm (m, 2H, CH2OH); 3.3 ppm (t, 2H, OCH2CH2 --); 1.4-2.6 (m, 5H, 2×CH2, OH); 0.5-1.3 ppm (m, 6H, 2×CH3).