Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)=[C:2]=[O:3].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][C:23]([C:25]([NH:27][CH:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])=[O:26])=[N:22][CH:21]=2)=[CH:16][CH:15]=1>>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([NH:1][C:2](=[O:3])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][C:23]([C:25]([NH:27][C@@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])=[O:26])=[N:22][CH:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: O=C=Nc1ccc2c(c1)CCC2
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc4c(c3)CCC4)cc2)o1)C(C)C
Yield: 92 %

Procedure:
The title compound was synthesized analogous to Example 1, using 5-isocyanato-2,3-dihydro-1H-indene (84.87 mg, 0.533 mmol) and intermediate 1. Yield: 92%; 1H NMR (DMSO-d6, 300 MHz): δ 9.005-8.978 (d, 1H), 8.912 (s, 1H), 8.624 (s, 1H), 7.804 (s, 1H), 7.781-7.752 (d, J=8.7 Hz, 2H), 7.617-7.587 (d, J=9 Hz, 2H), 7.395 (s, 1H), 7.172-7.106 (m, 2H), 4.328-4.277 (m, 1H), 3.681 (s, 3H), 2.860-2.772 (m, 4H), 2.286-2.217 (m, 1H), 2.052-2.154 (m, 2H), 0.980-0.928 (d, J=6.9 Hz, 6H); MS (ESI) m/z 475 [M−H], 477 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[CH:6][C:5]=1[Cl:16].C(O)=[O:19]>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10](=[O:19])[CH3:11])[CH:7]=[CH:6][C:5]=1[Cl:16]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1Cl
Reactant: O=CO
Product: COC(=O)c1cc(C(C)=O)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-trimethylsilanylethynyl-benzoic acid methyl ester (3.2 g, 12 mmol) in formic acid (50 mL) was heated at reflux for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried, filtered and concentrated in vacuo to afford the title compound (1.4 g).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C([Li])CCC.F[C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>C1COCC1>[CH:1]([NH:4][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Isopropylamine (4.0 mL) was dissolved in THF (20 mL). This solution was cooled to 0° C. and n-butyllithium (2.5 M, 20 mL) was added. The reaction was stirred for 90 min and then transferred to a solution of 2-fluoro-5-(trifluoromethyl)benzoic acid (4.2 g) in THF (40 mL) at −78° C. This mixture was stirred for 15 min and then quenched with aqueous NH4Cl. The mixture was extracted with EtOAc (3×), and the organic layer was dried, filtered, and concentrated in vacuo. Flash chromatography of the resulting residue provided 2-isopropylamino-5-(trifluoromethyl)benzoic acid (2.4 g). MS found: (M+H)+=248.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]2[OH:12].S(=O)(=O)(O)[OH:26].C(O)(=O)C.OO>C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[CH:5]=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2=[O:12]
Reactant: CCCCCCCCCCCCc1ccc2c(Cl)cccc2c1O
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCC1=CC(=O)c2c(Cl)cccc2C1=O
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of 5.4 parts of 5-chloro-2-dodecyl-1-naphthalenol, 18 parts of 96% sulfuric acid, 71.5 parts of glacial acetic acid, and 29 parts of water was stirred at 70° C and 8.85 parts of cold 30% hydrogen peroxide was added dropwise over 8 hours. Stirring at 70° C was continued for another 17 hours. The mixture was cooled and an orange solid taken up in methylene chloride, and the extract washed with water, dried and stripped. The resulting tan solid was purified by column chromatography from 1-chlorobutane on silica gel to give 2 parts of 5-chloro-2-dodecyl-1,4-naphthoquinone, m.p. 57.5°-58.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[NH2:14].[CH:19](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]2[N:14]=[CH:19][NH:13][C:8]=2[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=CO
Reactant: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1N
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]cnc23)c1

Procedure:
A solution of 3-(3-bromo-5-chlorophenoxy)-4-chlorobenzene-1,2-diamine (400 mg, 1.149 mmol) in 90% formic acid (5 mL) was heated to 100° C. for 1 hour. This mixture was concentrated in vacuo and then partitioned between ethyl acetate (40 mL) and sat. aq. NaHCO3 (40 mL). The organic extract was dried over MgSO4, filtered and concentrated in vacuo to give the desired compound. LRMS (M+1)=358.7.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([Li])CCC.[C:24]([N:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[C:28]1([CH2:27][O:26][C:24]([N:34]2[CH2:35][CH2:36][C:37]([OH:40])([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:1]([O:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:2])=[CH:13][CH:14]=3)[CH2:38][CH2:39]2)=[O:25])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Nc1ccc(Br)cc1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(carbobenzyloxy)-4-bromoaniline (5.00 g) in dry tetrahydrofuran (80 mL) at −78° C. under N2 is added n-butyllithium (21.4 mL, 1.6 M in hexanes) dropwise over five minutes. The resulting yellow solution is stirred at −78° C. for 30 minutes and is then treated with a solution of N-(carbobenzyloxy)-4-piperidone (3.99 g) in dry tetrahydrofuran (17 mL). The reaction mixture is stirred for three hours, during which the reaction temperature is allowed to rise to 0° C., and is quenched with saturated aqueous ammonium chloride (30 mL). The mixture is then diluted with water (100 mL), the layers are separated, the aqueous phase is extracted with diethyl ether, and the combined organic phase is washed with saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is chromato-graphed on silica gel (230-400 mesh, 350 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf=0.38 by TLC (ethyl acetate/hexane, 50/50) are pooled and con-centrated under reduced pressure by give the title compound, mp 156° C.-158° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:25])[C:6]([C:26]([O:28]CC)=O)=[C:5]2[SH:31])[CH2:3][CH2:2]1.[CH:32]1([N:35]2C3C(=CC(F)=C(F)C=3OC)C(=O)C3C(O)=C(C#N)SC2=3)C[CH2:33]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:25])[C:6]3[C:26]([OH:28])=[C:33]([C:32]#[N:35])[S:31][C:5]2=3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2c(OC(F)F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: COc1c(F)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Product: N#Cc1sc2c(c1O)c(=O)c1cc(F)c(N3CCNCC3)c(OC(F)F)c1n2C1CC1

Procedure:
The title compound is prepared from ethyl 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-2-mercapto-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate using the method described above for the preparation of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@@H:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[Br:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][C:25]=1[F:33]>CCOC(C)=O>[Br:23][C:24]1[N:29]=[C:28]([C:30]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@@H:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)=[O:31])[CH:27]=[CH:26][C:25]=1[F:33]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2N)C1
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C1

Procedure:
Following Method 9, tert-butyl (1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexylcarbamate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, tert-butyl (1S,3R,5S)-3-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-methylcyclohexylcarbamate was obtained. LCMS (m/z): 507.1/509.1 (MH+), Rt=0.90 min.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][C:16](OC(C)=O)=[O:17].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:16]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@H:2]([CH3:1])[CH2:7]1)(=[O:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-tert-butyl 2-methylpiperazine-1-carboxylate (4.8 g, 23.97 mmol), Ac2O (3.39 mL, 36.0 mmol) and pyridine (3.88 mL, 47.9 mmol) in DCM (30 mL) was stirred at rt for 30 min. Reaction was diluted with EtOAc, washed with diluted HCl, brine and sat NaHCO3, brine, and dried over Na2SO4, concentrated. Resulting residue was treated with 1N NaOH in ether, extracted with ether, washed with brine, dried over Na2SO4, concentrated and purified by FCC (0-10% MeOH in DCM) to give (R)-tert-butyl 4-acetyl-2-methylpiperazine-1-carboxylate. 1H NMR (400 MHz, CD2Cl2) δ ppm 4.14-4.46 (m, 2 H) 3.74-3.91 (m, 1 H) 3.46-3.72 (m, 1 H) 2.92-3.35 (m, 2 H) 2.56-2.91 (m, 1 H) 2.05 (d, J=16.67 Hz, 3 H) 1.44 (s, 9 H) 1.03-1.18 (m, 3 H). MS (ESI+) m/z 243.2 (M+H)+.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1.O>O1CCCC1.CN(C)C=O>[NH:16]1[C:15]([NH:14][C:1](=[O:13])[C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[N:19][N:18]=[N:17]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Quinaldic acid (1.1 g) in tetrahydrofuran (50 ml) containing dimethylformamide (5 ml) was treated with a solution of N,N'-carbonyl diimidazole (1 g) in tetrahydrofuran (40 ml) containing dimethylformamide (5 ml). After 3 hours, 5-aminotetrazole (0.65 g) in dimethylformamide (30 ml) was added and the resulting solution was stirred for 2 days at room temperature. The solvent was distilled off under reduced pressure to give an oil which solidified on trituration with water, m.p. 258° (d).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8]C)=[O:6])=[N+:2]=[N-:3].[C:10]([O:14][P:15]([CH:22]([OH:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11].C[O-].[Na+].[Cl-].[Na+].O.CCOC(C)=O>CO>[N:1]([C:4](=[CH:27][C:26]1[CH:25]=[CH:24][C:23]([CH:22]([P:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16])[OH:31])=[CH:30][CH:29]=1)[C:5]([O:7][CH3:8])=[O:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(O)c1ccc(C=O)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)C(=Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)N=[N+]=[N-]
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6.45 g (50 mmol) of ethyl α-azidoacetate and 1.64 g (5.0 mmol) of 4-[bis(tert-butoxy) -phosphorylhydroxymethyl)benzaldehyde 6 in MeOH (20 mL) at -78° C. was added a total of 7.4 mL (40 mmol) of NaOMe, 5.4M in MeOH, dropwise over 5 minutes. The mixture was stirred 5 minutes at -78° C. then an additional 1 hour at 0° C. The resulting light yellow suspension was subjected to an extractive work up (brine/EtOAc) to yield a light yellow crystalline solid, which was triturated with CHCl3 /pet. ether (35°-60° C.) to yield 7 as light yellow crystals, 1.26 g (57%), mp 111°-113° C.
Reaction SMILES: [C-]#N.[K+].Cl[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:18][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:19]=1.[CH3:20][N:21](C)C=O>O>[C:20]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:18][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:19]=1)#[N:21]
Reactant: ClCc1ccc2c(c1)Cc1cccnc1O2
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1ccc2c(c1)Cc1cccnc1O2
Reaction time: 2 h

Procedure:
A solution of 7.8 g of potassium cyanide in 20 ml of water is added dropwise to a mixture of 23 g of 7-chloromethyl-5H-[1]benzopyrano[2,3-b]-pyridine and 200 ml of dimethylformamide. The mixture is allowed to stand at 55°-60°C for 2 hours, and then poured into a large amount of water. The resulting crystalline precipitate is filtered off, washed with water, and recrystallized from aqueous dioxane to give 20 g of 7-cyanomethyl-5H-[1]-benzopyrano[2,3-b]pyridine melting at 166°-167°C.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([CH2:36][S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1>C1COCC1.O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:36][S:37]([NH:10][C:9]2[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]3[S:12][C:2]([CH3:1])=[C:3]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[C:4]=23)(=[O:39])=[O:38])=[CH:41][CH:42]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccc(Cl)cc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of 4-chlorobenzylsulfonyl chloride (198 mg, 0.879 mmol). The reaction mixture was then stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was stirred at RT for 1 h before the addition of 4-chlorobenzylsulfonyl chloride (79.2 mg, 0.352 mmol). The reaction mixture was stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (22 mg). LCMS (A) m/z: 473 [M+1]+, Rt 1.42 min (basic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([O:27][CH2:28][CH3:29])[N:18]=1.Cl>C(O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:19]1[N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=1)[CH3:29]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CCOc1cc(C(C)(C)O)nc(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C(C)(C)O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 10.4 %

Procedure:
A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (102 mg, 0.5 mmol), 2-(2-chloro-6-ethoxy-pyrimidin-4-yl)-propan-2-ol (108 mg, 0.5 mmol) and 1 N aqueous hydrochloric acid (0.025 mL) in ethanol (0.8 mL) was heated in a sealed tube in a microwave oven to 170° C. for 45 min. The mixture was cooled, diluted with ethyl acetate (50 mL), and then washed with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% ethanol as eluent to give the title compound (20 mg, 10%) as yellow foam. MS ISP (m/e): 384.3 [(M+H)+].)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.20, 7.78, 7.75 and 7.63 (4 d, 4×2H), 7.31 (s, 2H), 7.16 (s, 1H), 3.93 (s, 1H), 2.53 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:21]=[C:5]2[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:22]1([CH2:27][CH2:28][N:29]2[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]2)[CH2:26][CH2:25][CH2:24][CH2:23]1.Cl>O1CCOCC1>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:32]4[CH:31]=[N:30][N:29]([CH2:28][CH2:27][N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:33]=4)[N:21]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18].[ClH:1].[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:32]4[CH:31]=[N:30][N:29]([CH2:28][CH2:27][N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH:33]=4)[N:21]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Nc1cnn(CCN2CCCC2)c1
Reactant: CS(=O)(=O)c1ccc(Oc2cccn3nc(Cl)nc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cnn(CCN5CCCC5)c4)nc23)cc1
Product: CS(=O)(=O)c1ccc(Oc2cccn3nc(Nc4cnn(CCN5CCCC5)c4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine was synthesized from 2-chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (0.100 g, 0.309 mmol) and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine (0.072 g, 0.402 mmol) in a manner analogous to Example 2d. The isolated pure product was treated with 2N hydrogen chloride in dioxane. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine hydrochloric acid salt was isolated as a tan solid (81 mg, 56%). MP=Softened at 146-149° C. then melted at 215-217° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.55 (brs, 1H), 9.45 (s, 1H), 8.66 (d, J=6.26 Hz, 1H), 7.89 (d, J=8.13 Hz, 2H), 7.82 (s, 1H), 7.48 (s, 2H), 7.46 (s, 1H), 7.22 (d, J=8.23 Hz, 2H), 7.02 (t, J=6.93 Hz, 1H), 4.48 (brs, 2H), 4.18 (brs, 3H), 3.585 (d, J=4.90 Hz, 2H), 3.43 (brs, 2H), 2.92 (brs, 2H), 1.95 (brs, 2H), 1.82 (brs, 2H). MS=468 (MH)+.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:17]=1>ClCCl.C(OCC)(=O)C>[C:12]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C:18]1[N:17]=[C:16]([NH2:15])[CH:21]=[C:20]([CH3:22])[CH:19]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)nc(CCCCN)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCCc1cc(C)cc(N)n1
Reaction time: 48 h
Yield: 44 %

Procedure:
Triethylamine (0.059 mL, 43 mg, 0.42 mmol) and acetic anhydride (0.029 mL, 31 mg, 0.031 mmol) were added to a solution of 50 mg (0.028 mmol) of 2-amino-6-(4-aminobutyl)-4-methylpyridine (from Example 56) in 1.0 mL of dichloromethane. The solution was allowed to stand for 48 h at room temperature, then diluted with 25 mL of ethyl acetate and washed with 12 mL of saturated aqueous sodium bicarbonate and 12 mL of saturated aqueous sodium chloride. The aqueous layers were extracted in succession with 15 mL of ethyl acetate. The combined organic layers were dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 3.5 g of silica gel, eluting with 100 mL of 5% methanol in dichloromethane to give 27 mg (44% yield of 6-(4-acetamidobutyl)-2-amino-4-methylpyridine as an oil which spontaneously crystallized.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>O>[C:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][CH:3]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(C(=O)Cl)cc1

Procedure:
Monomethyl terephthalate (10.2 g, 0.057 mol) and thionylchloride (50 ml) were mixed in a 100 ml three-necked flask and stirred under gentle reflux overnight. The cooling water was shut off and excess thionylchloride swept away in a stream of nitrogen. By raising the temperature, the product then was distilled and collected as white crystals of high purity.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>C(O)C.[Pd]>[C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC=CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(=O)O
Yield: 99 %

Procedure:
A solution of 5(Z)-7- [2,4,5-cis]-2-methyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (500 mg.) in absolute ethanol (10 ml.) containing 5% w/w palladium on charcoal catalyst (100 mg.) was stirred under an atmospheric pressure of hydrogen for 3 hours. The catalyst was separated by filtration through kieselguhr and the filtrate was evaporated to give 5(Z) 7- [2,4,5-cis]-2-methyl-4-phenyl-1,3-dioxan-cis-5-yl)heptanoic acid as a colourless oil in 99% yield; NMR: 0.8-1.8 (14H,m), 2.2 (2H,t,J=8 Hz), 3.8-4.25 (2H,m), 4.75-5.0 (2H,m), 7.14-7.4 (5H,m) and 8.5-9.3 (1H,br)pm; m/e: 307 (M+ +H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:21][CH2:20]2.[Li+].[OH-].O.Cl>C1COCC1.CCO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:20]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)cc4)oc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)O)c(C)o2)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
Ethyl 2-((1S)-5-[2-{5-methyl-2-(4-methylphenyl)(1,3-oxazol-4-yl)]ethoxy}indanyl)acetate (Example 136, 776.3 mg, 1.85 mmol) in THF (4.0 ml) was added to a mixture of aqueous LiOH (2 M, 3.7 ml, 7.4 mmol), water (2.0 ml), and EtOH (4.0 ml) at rt. The resulting mixture turned cloudy. This mixture was heated at 40° C. (oil-bath temperature). The reaction was completed after 1.5 hours. After cooling to rt, 1 N HCl solution was slowly added to the mixture until pH 4.0. The compound was extracted with EtOAc (3×20 ml). The combined EtOAc layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue gave 2-((1S)-5-{2-[5-methyl-2-(4-methylphenyl)(1,3-oxazol-4-yl)]ethoxy}indanyl)acetic acid (616.8 mg, 1.57 mmol, 85%) as a white solid. 1H NMR (CDCl3) δ 7.83(d, 2H), 7.21(d, 2H), 7.03(d, 1H), 6.74(d, 1H), 6.69(dd, 1H), 4.19(t, 2H), 3.45(q, 1H), 2.93(t, 2H), 2.78(m, 2H), 2.51(m, 2H), 2.30(s, 3H), 2.25(s, 3H), 1.53(m, 2H).