Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:31][C:28]3[CH:29]=[CH:30][C:25]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[CH:26][CH:27]=3)[N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1

Procedure:
A mixture of 3-(4-Chloromethyl-thiazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (From Step 1) (775 mg, 2.56 mmol), 4-tetrazol-1-yl-phenol (415 mg, 2.56 mmol), CsCO3 (1.25 mg, 3.84 mmol) and KI (44 mg, 0.26 mmol) in acetonitrile (20 mL) was heated under reflux overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.63 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.24 (2H, s), 3.87 (1H, m), 3.79 (1H, m), 3.65 (2H, m), 3.45 (1H, m), 2.40 (1H, m), 2.23 (1H, m), 1.47 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9](F)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24].CCN(C(C)C)C(C)C.[NH:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1>CC(N(C)C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9]([N:35]3[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: OC1CCNCC1
Reactant: Cc1cc2cn[nH]c2cc1-c1cc(F)cc2c(N)c(C(N)=O)nnc12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2cn[nH]c2cc1-c1cc(N2CCC(O)CC2)cc2c(N)c(C(N)=O)nnc12
Temperature: 140 °C
Yield: 24.4 %

Procedure:
The mixture of 4-amino-6-fluoro-8-(5-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide (200 mg, 0.59 mmol), DIPEA (1000 mg), piperidin-4-ol (573 mg) and DMA (4 mL) was heated at 140° C. in a microwave under N2 for 3 h. The mixture was cooled, concentrated and purified directly with prep-HPLC to give the title compound as solid (60 mg, yield=24%). 1H NMR (400 MHz, DMSO-d6): δ 12.93 (1H, s), 8.27 (1H, s), 8.02 (1H, s), 7.60 (1H, s), 7.48-7.47 (3H, m), 7.35 (1H, s), 4.74 (1H, d, J=4.4 Hz), 3.89-3.86 (2H, m), 3.75-3.72 (m, 1H), 3.17-3.12 (2H, m), 2.00 (3H, s), 1.87-1.84 (2H, m), 1.53-1.49 (2H, m); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 2.809 minutes); ESI+APCI m/z [M+H]+ 418.
Reaction SMILES: Cl.Cl[CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27][CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: Sc1ccccc1Cl
Reactant: COc1ccc(CCC(Cl)Cn2ccnc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(CCC(Cn2ccnc2)Sc2ccccc2Cl)cc1
Reaction time: 8 h

Procedure:
A mixture of 1-[2-chloro-4-(4-methoxyphenyl)-n-butyl]imidazole hydrochloride (prepared from 2.00 g. of alcohol as in Preparation C), 2-chlorothiophenol (2.80 g) and anhydrous potassium carbonate (2.70 g) in acetone (50 ml) was heated under reflux with stirring overnight. After removal of the solvent under reduced pressure, ether (150 ml) was added and the extract washed with water (2×30 ml) and dried (MgSO4) and the solvent removed to afford 1-[2-(2-chlorophenylthio)-4-(4-methoxyphenyl)-n-butyl]imidazole. Dropwise addition of 70% nitric acid (d-1.42) to an ethereal solution of this material until precipitation was complete gave the nitrate salt of 1-[2-(2-chlorophenylthio)-4-(4-methoxyphenyl)-n-butyl]imidazole, recrystallized from acetone/ethyl acetate as colorless microcrystals (3.10 g), mp 131.5°-133.5° C.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([NH:23]C(=O)C)([CH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12])C(OCC)=O)C.Cl>C(O)(=O)C>[NH2:23][CH:5]([CH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(C)c1cccc2ccccc12
Agent: Cl
Solvent: CC(=O)O
Product: CC(c1cccc2ccccc12)C(N)C(=O)O
Yield: 73.2 %

Procedure:
A solution of 2-acetylamino-2-[1-(1-naphthyl)ethyl]propanedioic acid diethyl ester (21.59 g) in a mixture of concentrated hydrochloric acid (100 ml) and acetic acid (70 ml) was refluxed for 13 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in water (100 ml). The soluiton was neutralized to pH 5 with 30% sodium hydroxide. The precipitated crystalline solid was collected by filtration to give 2-amino-3-(1-naphthyl)butyric acid (9.76 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2=[N:15][C:16]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]2=3)[CH2:10][C@@H:9]1[CH2:30][C:31]([OH:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:46][CH:47](O)[CH2:48][C:49]([OH:52])([CH3:51])[CH3:50]>CN(C=O)C.CN(C)C1C=CN=CC=1>[Cl:29][C:27]1[CH:26]=[CH:25][C:17]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([CH2:30][C:31]([O:33][C@@H:47]([CH2:48][C:49]([OH:52])([CH3:51])[CH3:50])[CH3:46])=[O:32])[CH2:10]3)=[N:15][C:16]=2[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)C[C@@H]1CC(=O)O
Reactant: CC(O)CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](CC(C)(C)O)OC(=O)C[C@H]1CN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
(S,E)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acetic acid (300 mg, 0.60 mmol) can be dissolved in DMF (0.25M). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol), and 4-Dimethylaminopyridine (0.3 mmol) may be added respectively at room temperature under nitrogen. After about fifteen minutes R-(−)-2-Methyl-2,4-pentanediol (0.60 mmol) may be added and the mixture heated to about 50° C. under nitrogen. The product can be worked up as usual and purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate as a white foam. The (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate may be dissolved in anhydrous THF and cooled in a dry ice acetone bath under nitrogen. A 2.0M solution of Butyl lithium in cyclohexane (about 1 mole equivalent) may be added dropwise under nitrogen. After about 15 minutes, iodomethane (about 1 mole equivalent) may be added dropwise under nitrogen. After about one hour, a 2.0M solution of Butyl lithium in cyclohexane (about 1 equivalent) may be added dropwise under nitrogen. After about 15 minutes, iodomethane (about 1 equivalent) may be added dropwise under nitrogen. After about one hour the solution may be concentrated under vacuum to give (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(1-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate as a white foam. The (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(1-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate may be dissolved in dichloromethane (about 1.1 ml) and cooled in an ice bath. Trifluoroacetic acid (about 0.5 ml) may be added dropwise under nitrogen and slowly allowed to reach room temperature while running overnight. The mixture may be concentrated under vacuum and purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give Compound EK.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[C:4]([Cl:14])[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O>CO>[Cl:14][C:4]1[CH:3]=[C:2]([N:1]=[CH:19][C:18]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([F:15])[CH:17]=2)[CH:7]=[C:6]([Cl:8])[C:5]=1[N:9]=[CH:10][N:11]([CH3:12])[CH3:13]
Reactant: CN(C)C=Nc1c(Cl)cc(N)cc1Cl
Reactant: COc1ccc(C=O)cc1F
Solvent: CO
Product: COc1ccc(C=Nc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1F
Temperature: 5 °C

Procedure:
A 7.0 g. amount of N'-(4-amino-2,6-dichlorophenyl)-N,N-dimethylformamidine and 4.6 g. of 3-fluoro-p-anisaldehyde are each dissolved separately in 25 ml. of warm methanol and then combined. The mixture is cooled at 5° C. The crystallized product is collected and washed with ether to provide 8.2 g. of the product of the Example as yellow crystals, m.p. 139°-141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][N:7]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:41])=[CH:19][N:18]=1>>[C:12]([N:7]1[C:6]2[CH:15]=[C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[C:33]([F:34])=[CH:32][C:31]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:41])=[CH:19][N:18]=3)[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCCOc2ccc(N)cc21
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)N(C(C)=O)CCCO3)ncc1Cl

Procedure:
2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 1-(2-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a pale yellow solid (140 mg, 72%). m.p.=172-177° C.; LCMS (m/e) 565 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.85 (bs, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.89-7.81 (m, 2H), 7.45 (s, 1H), 7.38 (d, 1H, J=11.5 Hz), 7.03-6.87 (m, 3H), 6.60-6.50 (m, 1H), 4.65-4.50 (m, 1H), 4.43-4.29 (m, 1H), 4.01 (s, 3H), 3.63-3.47 (m, 1H), 3.00 (d, 3H, J=4.8 Hz), 2.55-2.37 (m, 1H), 2.23-2.06 (m, 1H), 1.87 (s, 3H), 1.72-1.57 (m, 1H); 19F-NMR (CDCl3, 400 MHz) δ −111.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27](O)=[O:28])[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([C:23]3[N:18]4[N:17]=[C:16]([NH:15][C:12]5[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)=[CH:10][CH:11]=5)[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=3)[CH:25]=2)=[CH:37][CH:36]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid (50 mg, 0.113 mmol), 4-chlorobenzylamine (27.5 μL, 0.226 mmol), EDC (44 mg, 0.226 mmol) and di-isopropylethylamine (98.5 μL, 0.564 mmol) was added HOBt (31 mg, 0.226 mmol). The mixture was stirred overnight at room temperature, and the desired product purified by preparatory HPLC. RT: 4.63 min, MI: 567.31, Method: basic. 1H NMR (DMSO, 300 MHz): 9.43 (s, 1H), 9.22 (t, 1H), 8.58 (s, 1H), 8.19 (t, 1H), 8.03 (d, 1H), 7.63 (m, 6H), 7.36 (s, 3H), 7.24 (dd, 1H), 6.84 (d, 2H), 4.50 (d, 2H), 3.99 (t, 2H), 2.81 (t, 2H), 2.50 (d, 2H), 2.36 (s, 2H), 1.69 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:24][C:25](=O)[CH3:26].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:24]=[C:25]([CH3:26])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1cc(Oc2cccc3ncccc23)c(Br)cn1
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3cccc4ncccc34)c(Br)cn2)n1
Yield: 77.2 %

Procedure:
A mixture of 1-(5-bromo-4-(quinolin-5-yloxy)pyridin-2-yl)thiourea (2.00 g, 5.330 mmol), 1-chloropropan-2-one (0.6366 ml, 7.995 mmol), triethylamine (1.486 ml, 10.66 mmol), and ethanol (25 ml) was heated at reflux for two days. The organic solvents were concentrated, and hexanes:ethyl acetate (9:1) were added and the reaction was filtered. The residue was washed with water and ethyl acetate, and dried over high vacuum overnight to give the desired compound (1.70 g, 76.40% yield) as very light yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=O)[CH3:21]>>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:20]1[CH3:21]
Reactant: COC(=O)CCCCCNC(C)=O
Reactant: O=[N+]([O-])c1ccccc1I
Product: COC(=O)CCCCCn1c(C)nc2ccccc21
Yield: 15.4 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and 6-acetylamino-hexanoic acid methyl ester (112 mg, 0.6 mmol) yielded the title compound as yellow oil (20 mg, 15%). 1H NMR (DMSO) δ 1.32-1.83 (m, 6H), 2.29 (t, J=7.1Hz, 2H), 2.80 (s, 3H), 3.55 (s, 3H), 4.38 (t, J=7.3, 2H), 7.48-7.56 (m, 2H), 7.76 (d, J=8.1Hz, 1H), 7.91 (d, J=8.1Hz).
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:52])[CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[C:28]3[S:36]([CH2:38][C:39]3[C:44]([CH3:45])=[C:43]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])[CH:42]=[CH:41][N:40]=3)=[O:37])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:15][CH3:16])(=O)=O)=CC=1.C([O-])(O)=O.[Na+:58]>CC#N.O>[Na+:58].[CH3:45][C:44]1[C:39]([CH2:38][S:36]([C:28]2[N:27]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH:14]([CH2:15][CH3:16])[C:13]([O-:52])=[O:12])=[CH:19][CH:20]=3)(=[O:25])=[O:26])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)=[O:37])=[N:40][CH:41]=[CH:42][C:43]=1[O:46][CH2:47][C:48]([F:50])([F:49])[F:51]
Reactant: CCC(Oc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1)C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(Oc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1)C(=O)[O-]
Yield: 56.8 %

Procedure:
A solution of 2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzoimidazole-1-sulfonyl}phenoxy)butyric acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 11, 400 mg, 0.50 mmol) and NaHCO3 (47 mg, 0.55 mmol, 1.1 eq) in CH3CN-H2O (7 mL-3 mL) was heated to 70° C. for 3 h. Then volatile materials were removed by evaporation and the residual gummy oil was dissolved in CH3CN. The CH3CN solution was filtered to remove un-dissolved solids. The filtrate was dried and the residual yellow foam was treated with ether-EtOAc (5:1) to precipitate a solid. The solid was again treated with CH3CN, and the CH3CN solution was filtered to give 180 mg (58%) of 2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)butyric acid sodium salt (Compound 4 sodium salt). The sodium salt was dissolved in water, and acidified to pH 3 by 1 N HCl solution, and extracted with dichloromethane. The dichloromethane layer was evaporated to give Compound 4 as a free acid, which was further purified on a short silica gel column to yield 125 mg of 2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]benzimidazole-1-sulfonyl}phenoxy)butyric acid (Compound 4).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=2)[CH2:57][CH2:56]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:66][C:65]3[CH:64]=[CH:63][C:62]([O:61][CH:58]4[CH2:59][CH2:60][N:55]([CH3:54])[CH2:56][CH2:57]4)=[CH:68][CH:67]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN1CCC(Oc2ccc(N)cc2)CC1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(NC(=O)c3cccc(N4CCc5nc(N)ncc5C4)c3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes 4-((1-methylpiperidin-4-yl)oxy)aniline (46 mg, 0.225 mmol) was added and the reaction continued at room temperature for 3 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with EtOAc to give the title compound as an off-white solid (48 mg, 70%). 1H NMR (DMSO-d6) δ: 10.02 (s, 1H), 8.13 (s, 1H), 7.60-7.67 (m, 2H), 7.49 (s, 1H), 7.30-7.40 (m, 2H), 7.20 (dt, J=7.7, 2.0 Hz, 1H), 6.90-6.96 (m, 2H), 6.40 (s, 2H), 4.28 (s, 2H), 4.26-4.35 (m, 1H), 3.64 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.56-2.66 (m, 2H), 2.17 (s, 3H), 2.10-2.21 (m, 2H), 1.86-1.97 (m, 2H), 1.55-1.69 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:15]2[CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCNCC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(C(=O)c2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
After 6-bromopicolinic acid (500 mg, 2.48 mmol) was suspended in acetonitrile (25 ml), 4-methylpiperidine (0.44 ml, 3.72 mmol), N,N-diisopropylethylamine (0.65 ml, 3.72 mmol), and HBTU (1.13 g, 2.97 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 4 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 677 mg of white solid (97%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4C=CC=CC=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)[CH3:40].C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([N:29]([CH2:39][CH3:40])[CH2:30][CH3:31])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:15]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Product: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 100 %

Procedure:
Following a procedure similar to that for the preparation of 1k, intermediate 1j (48 mg, 0.113 mmol), acetaldehyde (39.6 mg, 0.90 mmol) and NaBH(OAc)3 (216.2 mg, 1.02 mmol) yielded 56 mg (100%) of intermediate 3a. MS (ESI) 483.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C@H:29]1[OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@H:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C@H:29]2[OH:37])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: O=C(N[C@H]1c2ccccc2C[C@H]1O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)terephthalamide. MS (Q1) 518.2 (M)+.
Reaction SMILES: CS([CH2:5][CH:6]([CH3:18])[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)(=O)=O.[CH3:19][CH:20]1[O:25][CH:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>O>[CH3:26][CH:24]1[O:25][CH:20]([CH3:19])[CH2:21][N:22]([CH2:5][CH:6]([CH3:18])[CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[CH2:23]1
Reactant: CC(Cc1ccc2ccccc2c1)CS(C)(=O)=O
Reactant: CC1CNCC(C)O1
Solvent: O
Product: CC(Cc1ccc2ccccc2c1)CN1CC(C)OC(C)C1
Yield: 52.1 %

Procedure:
10.8 g (0.04 mol) of 1-methanesulphonyl-2-methyl-3-β-naphthylpropane and 9 g (0.078 mol) of 2,6-dimethylmorpholine are stirred at a bath temperature of 140° C. for 15 hours. Water is added to the resulting reaction mixture and the mixture is extracted several times with ether. The combined organic phases are dried over sodium sulphate and freed from the solvent in vacuo; the oily residue is purified by column chromatography (silica gel 60, petroleum ether/ethyl acetate=2:1). 6.2 g (52% of theory) of 1-(2,6-dimethylmorpholin-4-yl)-2-methyl-3-β-naphthyl-propane of refractive index nD20 =1.5527 are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(OC)c1OC
Yield: 34.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 5.00 g (29.4 mmol) of 5,6-diamino-1,3-dimethyluracil and 7.71 g (32.4 mmol) of 2,3,4-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from isopropanol/water to give 3.78 g (yield 35%) of Compound 82 as an ocher powder.