Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][NH:61][CH2:60][CH:59]5[CH:64]([CH3:66])[CH3:65])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:53].[ClH:1].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][N:61]([CH3:4])[CH2:60][CH:59]5[CH:64]([CH3:66])[CH3:65])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:33][CH2:34]1
Reactant: CC(C)C1CNCCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: CC(C)C1CN(C)CCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from racemic 2-{5-chloro-2-[3-(2-isopropyl-piperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 527 (35Cl) and 529 (37Cl) [M(free base)+H].
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([SH:11])[CH3:10].[NH2:12][C:13]1[N:21]=[C:20](Cl)[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cl-].[Na+].O>[NH2:12][C:13]1[N:21]=[C:20]([S:11][CH:9]([CH3:10])[CH3:8])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)S
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol 60% in mineral oil) were added 2-propanethiol (1.0 ml, 11 mmol) and 6-amino-9-benzyl-2-chloropurine (160 mg, 0.62 mmol) in order. The mixture was stirred under heating at 100° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (112 mg, yield 61%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.O.[OH-].[Ba+2:15].[OH-]>O>[C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=[O:6])[CH:3]=1.[Ba+2:15]
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cccc(C(=O)[O-])c1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
100 gms of isophthalic acid (0.6 mole) was slurried in 1 liter of water, the mixture heated to 90° C. and an equivalent amount of barium hydroxide monohydrate was added over a 25 minute period. The reaction mixture was kept at 90°-95° C. for an additional 45 minutes and allowed to cool at room temperature. Barium isophthalate was obtained in the form of long rods (with a length greater than 200 microns) and aspect ratios above 10. Anhydrous rods are produced by heating to dehydrate in a manner similar to the above examples.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17](F)[C:16]=1[N+:23]([O-:25])=[O:24])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH3:27]>CO>[C:1]([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH2:27])[C:16]=1[N+:23]([O-:25])=[O:24])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1[N+](=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
To the crude 2-(3,5-Difluoro-2-nitro-phenyl)-malonic acid di-tert-butyl ester (62 g, 0.42 mol) was added 700 mL of 2M ammonia in methanol in a pressure bottle. The vessel was sealed and heated to 85° C. for 18 hours. The reaction mixture was cooled and the vessel opened carefully and the methanol solution concentrated to provide 140 g of crude material. LCMS [M+Na]−393; 1H NMR (500 MHz, DMSO) δ 6.76 (dd, J=10.8 2.8 Hz, 1H), 6.29 (dd, J=10.8, 2.8 Hz, 1H), 4.99 (brs, 2H), 4.80 (s, 1H), 140 (m, 18H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH:21]=2)[N:17]=[C:16]2[N:33]([CH:36]([CH3:38])[CH3:37])[N:34]=[CH:35][C:15]=12)=[O:13]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.8 g, 5.4 mmol) in DCM (15 mL), TFA (13 mL) was added at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and residue neutralized with saturated NaHCO3 solution Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure, finally the residue was washed with diethyl ether to provide the desired intermediate (1.5 g, 66.4%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:8]([CH:11]=1)[CH:9]=[O:10]>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:8]([CH2:9][OH:10])[CH:11]=1
Reactant: COc1ccc(/C=C/c2ccc(F)cc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(/C=C/c2ccc(F)cc2CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
1.73 g (45.60 mmol) of sodium borohydride are added in portions to a solution of 7.79 g (30.40 mmol) of E-5-fluoro-2-[2-(4-methoxyphenyl)vinyl]benzaldehyde from Example 29A in 500 ml of methanol at 0° C., and the mixture is stirred at room temperature for 2 hours. After reaction is complete, the mixture is concentrated to dryness and then taken up in water and dichloromethane. The aqueous phase is then extracted twice more with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→1:1). 6.8 g (85% yield) of a colorless solid are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:17]([CH2:15][NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCC2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 45.9 %

Procedure:
A solution of 1,1-dimethylethyl 2-(aminomethyl)-1-pyrrolidinecarboxylate (1000 mg, 5 mmol) and methyl 4-formylbenzoate (820 mg, 5 mmol) in dichloroethane was stirred as acetic acid (450 mg, 7.5 mmol) and sodium triacetoxyborohydride (1271 mg, 6 mmol) were added sequentially at ambient temperature. After stirring at ambient temperature for 17 hours, treated with a saturated aqueous solution of sodium bicarbonate and extracted with EtOAc. The combined organic extracts were dried and concentrated. Purification by flash chromatography afforded 1,1-dimethylethyl 2-[[[[4-(methoxycarbonyl)phenyl]methyl]amino]methyl]-1-pyrrolidinecarboxylate (800 mg), 1H NMR (CDCl3) 7.98 (d, 2H), 3.37 (d, 2H), 3.91 (s, 3H), 3.82 (s, 2H), 3.36 (m, 2H), 2.72 (m, 1H), 1.82 (m, 3H), 1.44 (m, 2H) ppm.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH:7]=1)=[O:5].CO.[BH4-].[Na+].[NH3:33]>>[CH2:21]([N:18]1[CH2:17][CH2:16][CH:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH:4]([OH:5])[C:3]([NH2:33])=[O:2])=[CH:7]2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N
Reactant: COC(=O)C(=O)c1cn(C2CCN(Cc3ccccc3)CC2)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)C(O)c1cn(C2CCN(Cc3ccccc3)CC2)c2ccccc12
Yield: 103 %

Procedure:
Dissolve [1-(1-benzylpiperidin-4-yl)-1H-indol-3-yl]oxoacetic acid methyl ester (1.29 g, 3.43 mmol) in 2 M ammonia: methanol (35 mL) and stir at room temperature under nitrogen for 1.5 hours. Concentrate to a white solid and slurry into absolute ethanol (40 mL). Add sodium borohydride (0.65 g, 5 equiv) and stir 3 hours at room temperature under nitrogen. Concentrate then dilute with ethyl acetate and quench with water. Wash organic layer with brine. Dry over magnesium sulfate, filter and concentrate to give crude product (1.28 g, 103%). MS (ES, m/z): 364.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8]C(=O)C)=[C:6]([CH:12](O)[CH3:13])[C:5]([CH2:15][S:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1>COCCOCCOC>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:12]=[CH2:13])[C:5]([CH2:15][S:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1
Reactant: CC(=O)Oc1c(C)ncc(CSC(=O)c2ccccc2)c1C(C)O
Solvent: COCCOCCOC
Product: C=Cc1c(CSC(=O)c2ccccc2)cnc(C)c1O

Procedure:
The product from Step E (2 gm.) was added to diglyme and refluxed 3 hours. The mixture was evaporated to dryness to give 2-methyl-3-hydroxy-4-vinyl-5-benzoylthiomethylpyridine. This material was purified by chromatography on 800 gm. of silica gel by elution with 10% methanol in chloroform (v/v).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:42][C:39]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 641.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([Mg]Br)[CH2:23][CH2:22]1>C(Cl)Cl.C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of 3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-2-carbaldehyde (1.50 g, 5.21 mmol) in anhydrous CH2Cl2 (20 mL) at −76° C. under nitrogen was added dropwise cyclopropylmagnesium bromide (Boulder Scientific, 0.76 M, 20 mL, 15.2 mmol) in THF over 15 min. The reaction mixture was stirred at −70–50° C. for 1 h, quenched with aq. NH4Cl and 1 N HCl, and extracted with EtOAc (3×70 mL). The EtOAc layers were dried and concentrated. Purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1.5:8.5 to 1:4) gave the title compound as a pale oil (1.2 g, 70%): 1H NMR (CDCl3) δ 7.24 (m, 2H), 7.19 (m, 1H), 7.09 (m, 2H), 7.00 (d, 1H, J=4.4 Hz), 6.44 (d, 1H, J=4.4 Hz), 5.33 (q, 2H, AB), 4.10 (t, 1H, J=7.15 Hz), 2.62 (d, 1H, J=7.7 Hz), 1.40 (m, 1H), 0.51 (m, 2H), 0.32 (m, 1H), 0.14 (m, 1H); 13C NMR (CDCl3) δ 154.3, 150.5, 136.1, 129.0, 127.8, 126.2, 117.8, 117.3, 110.2, 108.6, 72.76, 44.6, 15.5, 3.0; MS (ESI+) 330.10 (M++H), 352.13, 354.13 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:50])[CH:5]=[C:6]([Cl:49])[C:7]=1[CH2:8][C@@H:9]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:10][C:11](=[O:33])[CH2:12][O:13]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C(Cl)Cl.Br>[Cl:49][C:6]1[CH:5]=[N+:4]([O-:50])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:10][C:11](=[O:33])[CH2:12][OH:13]
Reactant: O=C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Br
Solvent: ClCCl
Solvent: O
Product: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(trityloxy)acetoxy)ethyl)pyridine 1-oxide (4.0 g, 5.55 mmol) in DCM (1 Lt) cooled at 0° C., 160 drops of 48% HBr were added, and the reaction was stirred for 1 hour (temperature below 10° C.). Water was added to the mixture, the organic phase was separated, dried over Na2SO4 and evaporated under vacuum (bath temperature=25° C.). The crude compound was dissolved in DCM, and hexanes was added. The white precipitate thus formed was filtered and washed with plenty of hexanes. After drying, (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide was obtained (2.26 g, 4.73 mmol, 76% yield, MS/ESI+ 478.0 [MH]+) and used in the following step without further purification.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[N+:24]([C:27]1[CH:28]=[N:29][NH:30][CH:31]=1)([O-:26])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N+:24]([C:27]1[CH:28]=[N:29][N:30]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:31]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OCCc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(CCc2ccncc2)c1
Temperature: 0 °C

Procedure:
DIAD (7.27 mL; 37.2 mmol; 1.1 eq.) was added slowly into a solution of 4-(2-hydroxyethyl)pyridine (4.2 g; 34.1 mmol; 1.0 eq.), 4-nitro-1H-pyrazole (3.86 g; 34.1 mmol; 1.0 eq.) and triphenylphosphine (9.84 g; 37.5 mmol; 1.1 eq.) in THF (120 mL) maintained under nitrogen at 0° C. The reaction mixture was allowed to warm to RT and left O/N. THF was removed under reduced pressure and the crude was purified by flash chromatography on silica (EtOAc:heptane, gradient from 50:50 to 100:0) to afford the title compound in quantitative yield. MS (ESI+): 219.0, (ESI−) 272.1 (purity 92.2%). 1H NMR (400 Mz, DMSO-d6) δ 8.80 (s, 1H), 8.44-8.43 (m, 2H), 8.24 (s, 1H), 7.18-7.17 (m, 2H), 4.50-4.48 (t, J=7.04 Hz, 2H), 3.19-3.17 (t, J=7.0 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:24]=[C:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[S:19][C:1]([C:3]2[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)c1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 72.1 %

Procedure:
A mixture of tert-butyl 6-cyano-2-pyridinecarboxylate (1.1 g, 5.3 mmol), methyl thiosalicylate (1.8 g, 10.7 mmol), triethylamine (2.0 ml, 14.3 mmol) and toluene (4 ml) was refluxed for 12 hrs. After cooling, the precipitated crystals were collected by filtration, recrystallized from tetrahydrofuran-hexane to give the titled compound (1.3 g, 70%).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([CH3:30])[C:20]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:21][CH:22]=3)[C:17]2=[O:31])=[C:13]([CH3:32])[CH:12]=[C:11]([CH3:33])[N:10]=1)C1C=CC=CC=1.CCOC(C)=O.CO>[Pd].CO>[CH3:32][C:13]1[CH:12]=[C:11]([CH3:33])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([CH3:30])[C:20]([O:26][CH:27]([CH3:28])[CH3:29])=[CH:21][CH:22]=2)[C:17]1=[O:31]
Reactant: Cc1cc(C)c(CN2CCc3ccc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CN2CCc3ccc(OC(C)C)c(C)c3C2=O)c(=O)[nH]1
Yield: 76.2 %

Procedure:
A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-methyl-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (107b, 46 mg, 0.10 mmol) and 10% palladium on carbon (10 mg) in methanol (3 mL) was hydrogenated at 1 atmosphere using a balloon for 26 hours. The reaction mixture was filtered through CELITE® then the filtrate was concentrated under vacuum. The residue was purified by column chromatography (EtOAc/heptanes, 50/50-100/0 then EtOAc/MeOH, 100/0-70/30), to give the title compound (Example 107, 27 mg, 74% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (br. s., 1H), 7.05-7.01 (m, 1H), 6.99 (s, 1H), 5.87 (s, 1H), 4.58 (s, 2H), 4.51 (td, J=5.9, 12.1 Hz, 1H), 2.68 (t, J=6.0 Hz, 2H), 2.42 (s, 3H), 2.13 (s, 3H), 2.11 (s, 2H), 1.25 (d, J=5.9 Hz, 6H); MS 355 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)([O-])=O.[H][H]>[Ni].O1CCCC1>[C:18]1([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:12][CH2:13]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 31 parts of N-(2-nitrophenyl)-1-(phenylmethyl)-4-piperidinamine in 160 parts of tetrahydrofuran is hydrogenated at normal pressure and at a temperature of 40° C, with 20 parts of Raney nickel catalyst. After the calculated amount of hydrogen is taken up (3 moles) hydrogenation is stopped. The catalyst is filtered off and from the filtrate the solvent is evaporated. The solid residue is washed with 160 parts of 2,2'-oxybispropane, to yield 22 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine; mp. 112°-113° C. On concentrating the filtrate to about one quarter of its volume a second crop of 2.5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine is obtained; mp. 108°-109° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:6]([O:8][CH3:9])=[O:7])C.[Br:14][C:15]1[CH:20]=C[N:18]=[C:17](N)[CH:16]=1>CC(O)=O.O>[Br:14][C:15]1[CH:16]=[CH:17][N:18]=[C:1]([NH:2][CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:6]([O:8][CH3:9])=[O:7])[CH:20]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COC(=O)C(=CN(C)C)C(=O)OC
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(=CNc1cc(Br)ccn1)C(=O)OC
Yield: 52.7 %

Procedure:
A solution of dimethyl 2-((dimethylamino)methylene)malonate (11.5 g, 65 mmol, 2.2 equiv) and 4-bromopyridin-2-amine (5 g, 28.9 mmol, 1 equiv) in AcOH (40 mL) was stirred at room temperature for 24 h. Then the reaction mixture was diluted with water, filtered, the filter cake was dried to give 4.8 g of the desired product. MS (ESI): 315, 317 (MH+).
Reaction SMILES: [C:1]([C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[C:7]([CH3:12])=[N:6][C:5]=1[CH3:13])(=[O:3])[CH3:2].C[C:15]([N:17]([CH3:19])[CH3:18])=O>CN(C=O)C>[CH3:15][N:17]([CH3:19])[CH:18]=[CH:2][C:1]([C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[C:7]([CH3:12])=[N:6][C:5]=1[CH3:13])=[O:3]
Reactant: CC(=O)N(C)C
Reactant: CC(=O)c1c(C)nc(C)n1C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C)n(C(C)C)c1C(=O)C=CN(C)C
Yield: 13 %

Procedure:
5-Acetyl-1-isopropyl-2,4-dimethylimidazole (Method 8; 3g, 16.5 mmol) was dissolved in a mixture DMF.DMA (100 ml) and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The volatiles were evaporated in vacuo. The residue was purified by flash silica chromatography DCM:MeOH (increasing in polarity from 100:0 to 95:5) to give the title compound (510 mg, 13%) as an orange oil. NMR 1.38 (d, 6H), 2.18 (s, 3H), 2.30 (s, 3H), 2.83 (s, 3H), 3.08 (s, 3H), 4.72 (q, 1H), 5.21 (d, 1H), 7.46 (d, 1H); m/z 236
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:16]=[CH:15][C:9]3[O:10][C:11]([F:14])([F:13])[O:12][C:8]=3[CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[C:32]([CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[NH:30][CH:29]=[CH:28]2>ClCCl>[CH:1]1([CH:4]([C:6]2[CH:16]=[CH:15][C:9]3[O:10][C:11]([F:14])([F:13])[O:12][C:8]=3[CH:7]=2)[C:28]2[C:27]3[C:31](=[C:32]([CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:33]=[C:25]([F:24])[CH:26]=3)[NH:30][CH:29]=2)[CH2:3][CH2:2]1
Reactant: OC(c1ccc2c(c1)OC(F)(F)O2)C1CC1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
100 mg (0.44 mmol) of the compound from Example 157A and 0.04 ml (0.53 mmol) of trifluoroacetic acid were added to 100 mg (0.44 mmol) of the compound from Example 87A in 5 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 151 mg (78% of theory) of the title compound were obtained.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:26][C:27]([NH2:29])=[S:28])[CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:22]([NH:26][C:27]1[S:28][C:2]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:29]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CCCCNC(N)=S
Solvent: CCO
Product: CCCCNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2- (4-methylsulfonylphenyl) ethanone (Example 26, Step 2) (0.384 g, 1.03 mmol) in ethanol (15 mL) in a 25 mL round bottom flask was added N-butylthiourea (0.144 g, 1.09 mmol). The solution was heated to reflux for 14 hours and the reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and concentrated yielding 2-butylamino-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole (0.319 g, 77%) as an off-white fluffy solid: mp 134°-135° C., 1HNMR (DMSO d6) 7.94 (t, J=5.37 Hz, 1 H), 7.78 (d, J=8.79, 2 H), 7.45-7.36 (m, 4 H), 7.15 (t, J=8.79 Hz, 2H), 3.25 (q, J=5.37 Hz, 2 H), 3.18 (s, 3 H), 1.58-1.50 (m, 2 H), 1.41-1.32 (m, 2H), 0.90 (t, J=7.33 Hz, 3 H); MS (EI) m/z 404 (M+). HRMS Δ=1.1 mmu.