Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]C)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:41][CH2:42][CH2:43][CH2:44][NH2:45]>ClCCl>[NH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:19]([C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)=[C:10]([NH:9][CH2:8][CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:18]=1)=[O:21]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: NCCCN
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 100 °C
Yield: 58.4 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (0.35 g, 0.64 mmol) and 1,3-diaminopropane (0.45 g, 6.1 mmol) was heated at 100° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (80:20:1.2, by volume) changing to dichloromethane methanol:concentrated aqueous ammonia (88:12:2, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.22 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CCCCOc1ccc(CCNC)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: CCCCOc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1

Procedure:
This compound was prepared analogous to Example 5(b) by reaction of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(4-n-butoxy-phenyl)-ethyl]-amine.
Reaction SMILES: C(O)(=O)C.[CH:5]1([CH2:8][N:9]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:10]2[N:15]=[C:14]3[N:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[C:18]([CH3:19])[C:13]3=[CH:12][C:11]=2[CH:24]=O)[CH2:7][CH2:6]1.[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([CH2:42][NH2:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.C([BH3-])#N.[Na+]>CO>[F:30][C:31]([F:44])([F:45])[C:32]1[CH:33]=[C:34]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)[CH2:42][NH:43][CH2:24][C:11]1[CH:12]=[C:13]2[C:18]([CH3:19])=[N:17][N:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]2=[N:15][C:10]=1[N:9]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[CH2:8][CH:5]1[CH2:7][CH2:6]1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(C=O)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Reaction time: 0.33 h

Procedure:
Acetic acid (2.82 g, 46 mmol) was added to a mixture of 6-(bis(cyclopropylmethyl)amino)-1-(tert-butyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (8 g, 23 mmol) and (3,5-bis(trifluoromethyl)phenyl)methanamine (5.7 g, 23 mmol) in methanol at 0° C. The resulting mixture was stirred continuously for 20 min. Sodium cyanoborohydride (4.5 g, 70 mmol) was added portion wise to the reaction mixture at 0° C. and the mixture was stirred for 1 h. After which the mixture was quenched with water, organic layer was separated, washed with brine, dried and evaporated to obtain the title compound.
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.CS([O-])(=O)=O.[C:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:27](O)[CH:26]=[CH:25]2)(=[NH:21])[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CO.CN(C=O)C.N1C=CC=CC=1>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19](=[NH:20])[NH2:21])[CH:23]=3)[C:28]=2[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:10])=[CH:7][CH:6]=1
Reactant: NN=CNc1ccc(C(=O)O)cc1
Reactant: COC(=O)Cc1c(O)ccc2cc(C(=N)N)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)Cc1c(OC(=O)c2ccc(NC=NN)cc2)ccc2cc(C(=N)N)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
170 Milliliters of anhydrous pyridine and 72 ml of DMF were added to 8.1 g of 4-aminoiminomethylaminobenzoic acid.methanesulfonate, 10.0 g of 6-amidino-1-methoxycarbonylmethyl-2-naphthol.methanesulfonate, 71.6 g of DCC and 170 mg of DMAP, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. The precipitate was filtered and washed with a small amount of DMF. The filtrate and the wash liquid were combined and this was concentrated under reduced pressure. To the residue was added 50 ml of DMF, and the resulting solution was added dropwise to 700 ml of ether, followed by stirring for 24 hours under cooling with ice. The supernatant was decanted, and then to the residue was added 200 ml of acetone, followed by stirring for 1 hour under cooling with ice. The precipitate was collected by filtration to obtain a crude product. To the collected precipitate was added 300 ml of methanol to dissolve the precipitate. To the solution was added 2 g of active carbon, followed by stirring for 30 minutes at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added 100 ml of methanol to dissolve the residue with heating. The resulting solution was added dropwise to 300 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 4.2 g of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[CH2:29][CH2:28]OCC1>O>[CH3:10][NH:11][C:12]1[N:15]=[CH:29][C:28]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNc1ccc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Temperature: 90 °C
Yield: 61 %

Procedure:
A solution of Example A1 (0.380 g, 1.510 mmol) and 6-(methylamino)-3-pyridinylboronic (0.252 g, 1.661 mmol) in dioxane (8 mL) was sparged with Ar, treated with a solution of K2CO3 (0.417 g, 3.02 mmol) in water (2 mL) and heated at 90° C. for 16 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-methyl-4-((6-nitropyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-amine (300 mg, 61%) as an orange amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 8.73 (d, J=2.5 Hz, 1H), 8.58 (d, J=2.8 Hz, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.39 (d, J=8.9 Hz, 1H), 8.06 (dd, J=8.8, 2.5 Hz, 1H), 7.96 (dd, J=8.9, 2.9 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.00 (dd, J=5.6, 2.3 Hz, 1H), 6.87 (q, J=5.2 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 2.80 (d, J=4.7 Hz, 3H); MS (ESI) m/z: 324.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[K+]>C(O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:19]=[N+:20]=[N-:21])=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [K+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.1 %

Procedure:
A stirred suspension of 4-(4-chlorobenzoyl)-3-chlorobenzyl bromide (1.60 g, 4.65 mmol) and potassium azide (0.715 g, 8.81 mmol) in ethanol (15 ml) was refluxed 5 hours, cooled to ambient temperature, and stirred 16 hours. The solids were filtered and washed twice with ethanol. The combined filtrate and washes were evaporated under vacuum, diluted with diethyl ether (40 ml), filtered, and evaporated under vacuum to provide 1.51 g (106% of theory) of 4-(4-chlorobenzoyl)-3-chlorobenzyl azide, m.p. 33°-33.5° C., suitable for subsequent reaction.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([NH:19][CH3:20])=[C:10]2[S:15](O)(=[O:17])=[O:16])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)(Cl)[Cl:22].O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([NH:19][CH3:20])=[C:10]2[S:15]([Cl:22])(=[O:17])=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCc1cccc2c(S(=O)(=O)O)c(NC)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1cccc2c(S(=O)(=O)Cl)c(NC)ccc12
Temperature: 60 °C
Yield: 82.4 %

Procedure:
2 (23.9 g, 0.081 mol) was cooled with ice under nitrogen and mixed with phosphorus pentachloride (18.7 g, 0.0896 mol). The mixture was heated on a water bath at 60° C. for 2 hours and poured into a mixture of ice (164 g) and water (341 g). Ethyl acetate (400 mL) and sodium hydrogen carbonate (50 g, 0.60 mol) were added. The phases were separated and the water phase was extracted with ethyl acetate. The combined organic phases were washed, dried (sodium sulphate), and treated with activated carbon (1.1 g). Evaporation of the solvent gave 20.8 g of 3 as an oil. The product can be purified by chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][N:40]2[CH:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:56]=[CH:55][C:53]([NH2:54])=[C:52]([O:57][CH3:58])[CH:51]=2)[CH2:46][CH2:45]1.Cl.C[O-].[Na+]>C(O)C(F)(F)F.CO.C(Cl)Cl.C(OCC)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:54][C:53]3[CH:55]=[CH:56][C:50]([N:47]4[CH2:48][CH2:49][CH:44]([N:40]5[CH2:39][C@@H:38]6[CH2:43][C@H:41]5[CH2:42][N:37]6[CH2:36][CH2:35][F:34])[CH2:45][CH2:46]4)=[CH:51][C:52]=3[O:57][CH3:58])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4CCF)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4CCF)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 85 °C
Yield: 27 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (260 mg, 0.57 mmol) and 4-{4-[(1S,4S)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1-piperidinyl}-2-(methyloxy)aniline (200 mg, 0.57 mmol) in trifluoroethanol (2 mL) was added concentrated HCl (0.14 mL, 1.7 mmol). The reaction was heated in a sealed-tube at 85° C. for two days. After cooling to rt 0.5 N sodium methoxide in MeOH (4 mL) was added to the reaction. The solvent was removed under vacuum. DCM and silica gel were added, and the solvent removed under vacuum. The material was purified by flash chromatography. The desired fractions were combined and the solvent removed on the rotovap to give product. The material was dissolved in DCM then diethyl ether was added until the solution just turns cloudy. The solution was placed in the refrigerator. The title compound was obtained as yellow crystals which were collected by vacuum filtration, washing with ether. (120 mg, 0.15 mmol, 27% yield). 1H NMR (400 MHz, DMSO-d6) δ10.16 (s, 1H), 9.31 (brs, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.97 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.53 (dd, J=7.9, 7.7 Hz, 1H), 7.42-7.25 (m, 3H), 7.12 (dd, J=8.1, 8.1 Hz, 2H), 6.89 (dd, J=6.6, 6.6 Hz, 1H), 4.34 (dt, J=47.6, 4.9 Hz, 2H), 3.71 (s, 3H), 3.52 (d, J=11.7 Hz, 2H), 3.39 (s, 1H), 3.17 (s, 1H), 2.82-2.54 (m, 6H), 2.51 (d, J=9.3 Hz, 1H), 2.42-2.30 (m under DMSO peak, 2H), 1.78 (d, J=11.9 Hz, 1H), 1.69 (d, J=11.9 Hz, 1H), 1.50 (d, J=8.8 Hz, 1H), 1.42 (d, J=8.8 Hz, 1H), 1.38-1.25 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(O)cc1)C=Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(CCc1ccc(O)cc1)CCc1ccc(O)cc1
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A mixture of 20 g (0.075 mol) of 1,5-bis(4-hydroxyphenyl)penta 1,4-diene-3-one of Example 16 in 200 ml of glacial acetic acid and 1.5 g of 5% Pd/C was placed on a Parr hydrogenator for 2 hours under hydrogen. This reaction was repeated and the two solutions were filtered and evaporated to give a viscous oil (18 g). This was chromatographed on a silica gel column (Woelm) and eluted with CHCl3 :MeOH (95:5). The product (7.0 g) was recovered first and then 9.0 g of the corresponding alcohol.
Reaction SMILES: [O:1]1[C@@H:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C@@H:4]2[NH:3][S:2]1(=[O:14])=[O:13].[CH2:15](O)[C:16]#[CH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>CN(C)C=O>[CH2:17]([N:3]1[C@H:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:6][C@H:5]2[O:1][S:2]1(=[O:13])=[O:14])[C:16]#[CH:15]
Reactant: C#CCO
Reactant: O=S1(=O)N[C@H]2c3ccccc3C[C@H]2O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#CCN1[C@H]2c3ccccc3C[C@H]2OS1(=O)=O
Reaction time: 2 h
Yield: 37.4 %

Procedure:
To a stirred solution of 2.2 g (10.4 mmol) 8a in 120 ml dimethylformamide was added 1.35 ml (22.8 mmol) prop-2-yn-1-ol and 6 g (22.8 mmol) triphenylphosphin and 4.42 ml (22.8 mmol) dipropan-2-yl (E)-diazene-1,2-dicarboxylate. The reaction mixture was stirred for 2 h and concentrated. The residue was purified by two subsequent column chromatographies (ethyl acetate hexane1:20→2:1) to obtain 970 mg (37%) of the desired product 8b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:44]3[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCNCC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H34N4O3F3Cl2 [(M+H)+] 661.1955, observed 661.1947.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:30]([N:13]1[CH2:12][CH2:11][N:10]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:15][CH2:14]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
Diisopropylethylamine (0.24 ml, 1.36 mmol) was added in one portion to a stirred solution of N-[4-(piperazine-1-sulfonyl)-phenyl]-acrylamide (0.1 g, 0.34 mmol) in THF (5 ml). The mixture was stirred at room temperature for 5 minutes before benzoyl chloride (0.05 ml, 0.44 mmol) was added drop wise and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The crude reaction mixture was concentrated under vacuum and the residue was purified by Prep HPLC to give the title compound (0.018 g, 13% yield) as a white powder.
Reaction SMILES: C(#N)C.Cl.[CH3:5][N:6]([CH3:10])[CH2:7][CH2:8][SH:9].C[O-].[Na+].Cl[CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CO>[CH3:5][N:6]([CH3:10])[CH2:7][CH2:8][S:9][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CN(C)CCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)CC(=O)CSCCN(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
200 ml of acetonitrile was added to 28.3 g of 2-dimethylaminoethanethiol hydrochloride, and after 80 ml of sodium methoxide-containing 28% methyl alcohol solution was added thereto with cooling in an ice bath, 32.9 g of ethyl 4-chloroacetoacetate was dropwise added thereto with cooling in an ice bath. After the dropwise addition, the whole was stirred for 2 hours at 40° C., and then the inorganic salt was separated by filtration and the resulting filtrate was dried under reduced pressure. The oily substance obtained was purified by silica gel column chromatography (with moving phase solvent of chloroform/methyl alcohol, 10/1) to obtain 41.8 g of ethyl 4-(2-dimethylaminoethylthio)acetoacetate. To 23.3 g of the ethyl 4-(2-dimethylaminoethylthio)acetoacetate thus-obtained were added 8.4 g of 3-amino-1,2,4-triazole and 4.0 ml of acetic acid, and the whole was heated under reflux for 4 hours. After the reaction, 100 ml of methyl alcohol was added to the reaction solution and stirred with cooling in an ice bath, and the crystal precipitate was taken out by filtration and recrystallized from 300 ml of methyl alcohol to obtain 10.2 g of the desired product. M.P.: 109°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH:11]=1)[C:8]([NH:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)=[O:10]
Reactant: Nc1cccnc1
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
A solution of 5-(methyloxy)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 7; 280 mg, 1.08 mmol), 3-pyridinamine (204 mg, 2.17 mmol), EDC (312 mg, 1.63 mmol) and HOBT (249 mg, 1.626 mmol) in DMF (5 ml) was stirred under nitrogen at 25° C. overnight. The reaction mixture was then poured into water (20 ml), filtered and the solid was washed with water and dried to yield the title compound as a white solid. 150 mg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=4[CH3:33])[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1C
Solvent: Cc1ccccc1C
Product: Cc1nccc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)c1C

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K18) (244 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (140 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:18]2[NH:26][C:25]3[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=3[CH:19]=2)[N:3]=1.[CH3:28][C:29](OC(C)=O)=[O:30]>C(Cl)Cl>[C:29]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][C:11]2[C:2]([CH3:1])=[N:3][C:4]3[C:9]([N:10]=2)=[C:8]([C:18]2[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:14]1)(=[O:30])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCNC1
Solvent: ClCCl
Product: CC(=O)N1CC[C@H](Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.5 %

Procedure:
Prepared according to Example 50, using TEA (57.6 μl, 0.414 mmol), (S)-2-(2-methyl-3-(pyrrolidin-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 55, 125 mg, 0.345 mmol), Ac2O (65.1 μl, 0.690 mmol), and DCM (3.5 mL) stirring at 25° C. for 1.5 h. Purification by trituration with Et2O and elution through a Si-carbonate cartridge (Silicycle) provided (S)-2-(3-((1-acetylpyrrolidin-3-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (23 mg, 16.5%). 1H NMR (DMSO-d6) δ: 7.84-7.90 (m, 1H), 7.53-7.59 (m, 1H), 7.32-7.40 (m, 1H), 7.13-7.21 (m, 2H), 6.89-6.97 (m, 1H), 4.61-4.75 (m, 1H), 3.45-3.98 (m, 3H), 3.38-3.45 (m, 1H), 2.82-2.90 (m, 2H), 2.57 (s, 3H), 2.04-2.44 (m, 2H), 1.98 (s, 3H), 1.12-1.21 (m, 2H). m/z (ESI, +ve) 405.1 (M+H)+.