Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.CCN(CC)CC.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](Cl)=[O:34].N1C=CC=CC=1C=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:15]=[N:16][N:17]([C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[O:34])[CH:18]=1
Reactant: Cc1sc(Nc2ccccn2)nc1-c1cn[nH]c1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: O=Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1sc(Nc2ccccn2)nc1-c1cnn(C(=O)c2ccccn2)c1
Reaction time: 0.17 h

Procedure:
According to Scheme 21: To a solution of 5-methyl-4-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-2-amine (0.19 mmol, 50 mg) in DCM (2 mL) was added Et3N (0.78 mmol, 108 μL). After stirring for 10 minutes, picolinoyl chloride hydrochloride (0.39 mmol, 69.2 mg) was added. The reaction mixture was stirred for 3 hours at room temperature. The solvent was then removed under reduced pressure to afford a yellow solid. The crude mixture was solubilised in DMF. A white solid was precipitated, was filtered and was washed with MeOH. After evaporation, 4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)(pyridin-2-yl)methanone (50 μmol, 18 mg, 25%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:25][CH2:26][CH2:27][C:28]1[C:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][C:31]2[CH2:32][CH2:33][O:34][C:30]=2[CH:29]=1.CS(C)=O>O1CCCC1.O>[C:2]1([NH:1][CH2:25][CH2:26][CH2:27][C:28]2[C:36]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][C:31]3[CH2:32][CH2:33][O:34][C:30]=3[CH:29]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OCCCc1cc2c(cc1OCc1ccccc1)CCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(COc2cc3c(cc2CCCNc2ccccc2)OCC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a -78° solution of lithium anilide, prepared from aniline (0.217 g, 2.33 mmol) and n-butyllithium (1.6 M in hexane, 1.46 mL, 2.33 mmol), in tetrahydrofuran (2 mL) was added a solution of 8a (0.980 g, 2.23 mmol). Dimethyl sulfoxide (0.1 mL) was added and the mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ether (2 X). The extracts were dried (MgSO4) and concentrated to afford 12.
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[C:32]1([S:29]([NH:28][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([OH:38])=[O:5])(=[O:31])=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h

Procedure:
40.1 mg of (2S)-2-benzenesulfonylamino-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-propionic acid tert-butyl ester were dissolved in trifluoroacetic acid/water (95/5) and stirred for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in acetic acid/water and lyophilized. Yield 24 mg. MS (ES+): m/e=489.2 (M+H)+.
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@@H:14]2[CH:18]=[C:17]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH2:16][N:15]2[C:27]([O:29]CC2C=CC=CC=2)=[O:28])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=C1CN(C(O[C:46]([CH3:49])([CH3:48])[CH3:47])=O)[C@H](C(=O)N[C@H]2C3C(=CC=CC=3)CCC2)C1>>[C@H:1]1([NH:11][C:12]([C@@H:14]2[CH:18]=[C:17]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH2:16][N:15]2[C:27]([O:29][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:28])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Product: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 61 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound B of Example 22, (S)-tert-butyl 4-oxo-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate (3.38 g, 9.43 mmol) was converted to the title compound (2.82 g, 61%). MS (ESI+) m/z 491.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OC)=[O:16])[C@H:11]([O:19][CH3:20])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[AlH4-].[Li+]>CCOCC>[OH:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][C@H:11]1[O:19][CH3:20]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C[C@H]1OC
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CO[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl (1S,2R,4S)-4-[(tert-butoxycarbonyl)amino]-2-methoxycyclohexanecarboxylate (racemic) (0.87 g, 3.0 mmol) were dissolved in ether (27 mL) and cooled to 0° C. Lithium tetrahydroaluminate (138 mg, 3.63 mmol) was added and the resulting reaction mixture was stirred for 4 h. The reaction was quenched with 5 mL water at 0° C., then diluted with 5 mL 15% NaOH and 15 mL water after stirring for 30 min. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with flash chromatography (eluting with a gradient of 0-80% ethyl acetate in hexanes) to give the desired product as white foam.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:25])(=[O:24])[NH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[OH:23][CH:20]([CH2:21][OH:22])[CH2:19][NH:18][S:17]([C:4]1[S:3][CH:2]=[C:6]([C:7]2[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=2[CH3:16])[CH:5]=1)(=[O:25])=[O:24]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCC(O)CO)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)NCC(O)CO)c2)s1
Temperature: -70 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
N-{5-[2-Bromo-5-(2,3-dihydroxy-propylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (790 mg; 1.38 mmol; 1 eq), is dissolved in anhydrous THF (50 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (6.9 ml; 1.6 M; 11.0 mmol; 8 eq) is added dropwise. The reaction is stirred 2 hours and is quenched with water. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording Compound (40) as a light pink solid (224 mg; 42%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>>[CH2:17]([NH:20][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:18]=[CH2:19]
Reactant: C=CCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: C=CCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 186° C. and MS: m/e=251 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and allylamine.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.S(=O)(=O)(O)O.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>C(O)(=O)C>[OH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[I:1]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#Cc1ccc(O)c(I)c1

Procedure:
4-Hydroxy-3-iodobenzonitrile was prepared by the method analogous to Preparation 341 above using N-iodosuccinimide, acetic acid, sulfuric acid and 4-Hydroxybenzonitrile. Purified by ISCO™ (80 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[NH:27]1[CH2:30][CH:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:28]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:27]3[CH2:30][CH:29]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:28]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: C1CCN(C2CNC2)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CC(N4CCCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(azetidin-3-yl)piperidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (d, J=4.80 Hz, 2 H) 1.41-1.54 (m, 4 H) 2.23-2.34 (m, 3 H) 2.36 (s, 3 H) 3.13-3.21 (m, 1 H) 3.86 (dd, J=9.47, 4.67 Hz, 1 H) 4.05 (t, J=8.46 Hz, 1 H) 4.20 (d, J=4.80 Hz, 1 H) 4.28-4.43 (m, 1 H) 7.55 (dd, J=8.08, 1.52 Hz, 1 H) 7.62 (s, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 8.03 (s, 1 H) 8.15 (dd, J=8.72, 2.40 Hz, 1 H) 8.35 (d, J=8.84 Hz, 1 H) 8.65 (dd, J=2.27, 0.76 Hz, 1 H) 12.19-13.21 (m, 1 H); ESI-MS m/z [M+H]+ 443.3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c2) the title compound is obtained as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[N:3]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[C:4]([CH3:10])[N:3]=1
Reactant: NO
Reactant: Cc1nc(Cl)ccc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(Cl)ccc1C=NO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-Chloro-2-methylnicotinaldehyde (1 g, 6.43 mmol), hydroxylamine hydrochloride (0.45 g, 6.43 mmol), and sodium acetate (0.53 g, 6.43 mmol) were dissolved in dry ethanol (32 ml) and transferred to a flame-dried round bottom flask. The reaction was allowed to stir at room temperature for 20 minutes. It was then concentrated under reduced pressure, re-dissolved in ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate two times. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed via silica gel chromatography (0-100% ethyl acetate in hexane) to afford the title compound.
Reaction SMILES: N#N.[F:3][C:4]1[C:9]([C:10]2[CH2:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH:15]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.[ClH:23].CC(O)C>[Pd].CCO>[ClH:23].[ClH:23].[F:3][C:4]1[C:9]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1C=C(c2cccnc2F)CCC1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CC(C)O
Solvent: CCO
Product: Fc1ncccc1C1CCCNC1
Reaction time: 0.08 h

Procedure:
To a N2 purged RBF containing tert-butyl 5-(2-fluoropyridin-3-yl)-3,4-dihydropyridine-1(2H)-carboxylate (673 mg, 2.418 mmol) was added 10% Pd/C (50 mg, 0.470 mmol) and EtOH (15 mL). After stirring for 5 minutes, 5N HCl in iPrOH (4.0 mL, 20.00 mmol) was added and the flask capped with a balloon of H2. After 16 hours, LC-MS shows ˜30% conversion. The balloon was refilled. After a further 5 days, LC-MS shows complete consumption of starting material. The reaction was filtered through a celite cartridge and the cartridge rinsed with DCM:10% EtOH (50 mL). The filtrate was concentrated in vacuo to give 2-fluoro-3-(piperidin-3-yl)pyridine dihydrochloride as a yellow foam. The material was carried forward without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)=[CH:6][CH:7]=1.[C:21]([NH:24][NH2:25])(=O)[CH3:22]>C(O)CCC>[CH3:22][C:21]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:25][N:24]=1
Reactant: CC(=O)NN
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)nn2)cc1C(F)(F)F
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc([N+](=O)[O-])c(C(F)(F)F)c3)nn12

Procedure:
A mixture of 4.0 g. of 3-chloro-6-[4-nitro-3-(trifluoromethyl)phenyl]pyridazine and 1.95 g. of acetylhydrazine in 40 ml. of n-butanol is refluxed for 18 hours to give the product as crystals m.p. 293°-295° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]2OCC[O:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:25])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>Cl.O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]=[O:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:25])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nc(SCC2OCCO2)nc2c1nc(O)n2Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(SCC=O)nc2c1nc(O)n2Cc1ccccc1
Temperature: 70 °C
Reaction time: 7 h
Yield: 44.9 %

Procedure:
6-Amino-9-benzyl-2-(1,3-dioxolan-2-yl-methyl)thio-8-hydroxypurine (44 mg, 0.12 mmol) was dissolved in a mixture of 3.3N hydrochloric acid (1 ml) and tetrahydrofuran (4 ml). The solution was stirred at 70° C. for 7 hours and then neutralized with aqueous sodium hydrogen carbonate. After removal of tetrahydrofuran in vacuo, the resulting crystals were filtered, washed with water and repulped in methanol to give the subject compound (17 mg, yield 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:17])[CH:10]=[CH:11]1)[S:6]2.Cl.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:17])[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:11]1)[S:6]2
Reactant: COc1ccc2nc3ccc(=O)cc-3sc2c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)cc-3sc2c1
Temperature: 100 °C

Procedure:
A mixture of 7-methoxy-3H-phenothiazin-3-one (1.2 g) and N-methyl piperazine HCl (3.4 g) in DMF (20 ml) was heated at 100° C. for 3 hours. Then NaIO4 (1 g) was added and the reaction mixture was heated at 100° C. for 1 hour. Ice-water was added to the reaction mixture followed by ethyl acetate. The aqueous layer was decanted, filtered and the filtrate basified with K2CO3 and extracted with ethyl acetate. The organic layer was evaporated to dryness, the resulting residue was dissolved in CH2Cl2, dried and evaporated to dryness to afford the crude final product (1.2 g) which was purified by chromatography on silica gel column eluting with 10% MEOH/CH2Cl2 to give the title compound, m.p. 208°-209°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.N1C=CC=N1.C[NH:34][CH2:35][CH2:36][NH:37][CH3:38].CC(C)([O-])C.[K+]>[Cu]I.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([N:34]3[CH:35]=[CH:36][N:37]=[CH:38]3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(I)cc2)c1Sc1ccc(Cl)cc1
Reactant: CNCCNC
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-n3ccnc3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
To a microwave tube were added 2-[5-[(4-chlorophenyl)thio]-4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl]pyridine (Example 61, 150 mg, 0.30 mmol), CuI (57 mg, 0.30 mmol), pyrazole (61 mg, 0.89 mmol), N,N′-dimethylethylenediamine ((79 mg, 0.89 mmol), potassium t-butoxide (100 mg, 0.89 mmol), and 4 mL of NMP. The reaction was heated at 150° C. for 90 min via microwave. After filtration through Celite, the reaction mixture was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.65 (d, 1H), 8.37 (d, 1H), 8.24 (d, 2H), 7.98 (broad s, 1H), 7.84 (t, 1H), 7.43 (d, 2H), 7.36 (t, 1H), 7.25 (d, 2H), 7.04 (d, 2H), 4.15 (s, 3H). LCMS: m/z 444 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(C)[C@H]1CCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC[C@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N,N-dimethylpyrrolidin-3-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 2.09-2.30 (m, 1 H) 2.33 (d, J=2.27 Hz, 4 H) 2.76-2.93 (m, 6 H) 3.52-3.78 (m, 3 H) 3.83-4.00 (m, 2 H) 7.63 (d, J=7.83 Hz, 1 H) 7.74 (t, J=7.58 Hz, 1 H) 8.21 (d, J=7.58 Hz, 3 H) 8.67 (s, 1 H).). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][C@H:14]1[C@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:17][C@@H:16]([CH3:23])[CH2:15]1)(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].[C:24](OCC)(=[O:28])/[CH:25]=[CH:26]/[CH3:27]>C(O)(C)(C)C>[CH3:27][C@@H:26]1[CH2:25][C:24](=[O:28])[CH2:11][C:9](=[O:10])[C@H:8]1[C:7]([O:13][C@H:14]1[C@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:17][C@@H:16]([CH3:23])[CH2:15]1)=[O:12]
Reactant: CC(=O)CC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reactant: C/C=C/C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1C(=O)CC(=O)C[C@H]1C
Temperature: 23 °C

Procedure:
A 2-L 3-necked round bottom flask fitted with a reflux condenser, a mechanical stirrer, and a glass stopper was charged with t-butyl alcohol (300 mL) and potassium t-butoxide (68.7 g, 612 mmol, 1.04 equiv). The glass stopper was removed and, with efficient mechanical stirring, (1R, 3R, 4S)-p-menth-3-yl acetoacetate (1, 150 g, 624 mmol, 1.06 equiv) was added rapidly to the yellow slurry. The open neck of the reaction flask was fitted with a 100-mL addition funnel containing (E)-ethyl crotonate (73.2 mL, 588 mmol, 1 equiv). The largely solid reaction mixture was heated to reflux with a heating mantle. At this point, (E)-ethyl crotonate was added to the refluxing, dark yellow slurry over 15 min via the addition funnel. The addition funnel was replaced with a glass stopper and heating at reflux was continued. Solids were observed to dissolve within 1 h after addition of (E)-ethyl crotonate; the product began to crystallize from solution after about 1.5 h. After a total reflux period of 2.5 h (from addition of (E)-ethyl crotonate), heating was discontinued and the reaction mixture was allowed to cool to 23° C. The cooled reaction mixture was partitioned between aqueous sulfuric acid solution (5% v/v, 500 mL) and dichloromethane (600 mL). The aqueous layer was separated and extracted further with two 600-mL portions of dichloromethane. The combined organic layers were dried over sodium sulfate and then were concentrated. The solid residue was dissolved in boiling benzene (ca. 600 mL) and the resulting solution was allowed to cool slowly to 23° C. whereupon (1R, 3R, 4S)-p-menth-3-yl (1R, 2S)-2-methyl-4,6-dioxocyclohexanecarboxylate (2) crystallized as a white powder (mp 180°-181° C., 64.5 g, 36w). To isolate the diastereomeric diketone product, (1R, 3R, 4S)-p-menth-3-yl (1S, 2R)-2-methyl-4,6-dioxocyclohexanecarboxylate (3), the mother liquors were concentrated and the solid residue was dissolved in boiling ethyl acetate (ca. 200 mL). Hexanes (50 mL) were added to the hot solution and the mixture was allowed to cool to 23° C. Further cooling to -20° C. induced crystallization of diketone diastereomer 3 over a period of 12 h (mp 140°-141° C., 45 g, 25%).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)N.S(=O)(=O)(O)O.[N+]([O-])([O-])=O.[Na+].[I-:22].[K+]>O.[Cu]>[I:22][C:6]1[C:5]([CH3:11])=[C:4]([CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:2]
Reactant: [I-]
Reactant: Cc1c(N)cccc1CO
Agent: [Cu]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(I)cccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A stirred solution of 3-hydroxymethyl-2-methylaniline hydrochloride (43.4 g, 0.25 mole) and 17.2 ml of concentrated sulfuric acid in ice-water was cooled to 0°, and a solution of sodium nitrate (17.3 g, 0.25 mole) in water was added dropwise. Upon complete addition, the reaction mixture was stirred for an additional 0.5 hour, then an additional 8 ml of concentrated sulfuric acid was added dropwise. With the temperature maintained at 0°, a solution of potassium iodide (49.8 g, 0.30 mole) in water was added dropwise to the reaction mixture, followed by the addition of 0.1 gram of copper powder. The reaction mixture was slowly warmed to 70° where it stirred for 1 hour. The reaction mixture was then allowed to stand for 18 hours while cooling to room temperature. The reaction mixture was then taken up in water and extracted with chloroform. The chloroform extract was washed with an aqueous saturated solution of sodium bisulfite, then with water. The chloroform layer was dried and filtered. The filtrate was evaporated under reduced pressure to give 3-iodo-2-methylbenzyl alcohol (15.2 g) as a dark solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=1
Reactant: CS(=O)(=O)NCCn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)NCCn1cc(N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.1 %

Procedure:
To a solution of N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)methanesulfonamide (880 mg) obtained in Step A of Example 349 in ethanol (30 mL) was added 10% palladium-carbon (200 mg), and the mixture was stirred at room temperature for 3 hr under hydrogen atmosphere (at normal pressures). The palladium carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the title compound (860 mg).