Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[Ca+2].C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C=O
Agent: [Ca+2]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 220 °C
Yield: 85 %

Procedure:
p-Acetaminophenol 15 g, calcium carbonate 60 g, and solid catalyst Y-type molecular sieve 7.5 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 2.0 MPa and heated to 220° C., maintained for 1 hour, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve calcium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 96% and the yield is 85%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9](Br)[C:10]([O:13][CH:14](F)F)=[N:11][CH:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:18][O:19][C:20]1[N:25]=[C:24](B(O)O)[CH:23]=[CH:22][CH:21]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:13][C:10]1[C:9]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[N:25]=2)=[CH:8][C:7]([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:12][N:11]=1
Reactant: COc1cccc(B(O)O)n1
Reactant: FC(F)Oc1ncc(Cn2cncn2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: COc1cccc(-c2cc(Cn3cncn3)cnc2OC)n1
Temperature: 120 °C
Yield: 25 %

Procedure:
A solution of 5-((1H-1,2,4-triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine (Intermediate 13, 50 mg, 0.16 mmol), (6-methoxypyridin-2-yl)boronic acid (46 mg, 0.30 mmol), in EtOH (2.45 mL), benzene (7.00 mL), was combined with tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.02 mmol), and 4 M aqueous sodium carbonate (3 mL) in a microwave vial. The vial was sealed, purged with nitrogen and heated under microwave conditions to 120° C. for 12 minutes. Water was removed from the reaction with a pipette, and the crude reaction mix was filtered thru CELITE®, and washed with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 30-70% EtOAc/hexanes) afforded the title compound (11.9 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.58 (d, J=2.7 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.24 (s, 1H), 6.91-6.84 (m, 2H), 5.93 (d, J=4.3 Hz, 1H), 4.69 (s, 2H), 3.97 (s, 3H), 3.14 (s, 3H). [M+H]=298.02.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(N2N=C(c3ccc(OC)c(OC)c3)[C@H]3CC=CC[C@H]3C2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 20 mmol of 2-chloroethylsulfonylchloride in 20 ml of dichloromethane is added to a solution of 15 mmol of compound 5c and 25 ml of diisopropylethylamine in 50 ml of dichloromethane. The resulting mixture is stirred at RT for 18 h, after which it is washed first with diluted hydrochloric acid and then with a saturated solution of sodium bicarbonate. After drying over magnesium sulfate and evaporating the solvent, the compound is crystallised from diethyl ether. M. p. 89-90° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH:12]=1.[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[CH3:26]>C1COCC1>[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=3)=[O:35])=[CH:20][CH:19]=2)[CH:12]=1
Reactant: Nc1ccc(Cc2cc(Cl)ncn2)cc1
Reactant: CCc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(Cl)ncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4 N solution of HCl in dioxane (1.2 mL, 4.96 mmol, 30 equiv) is added to a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (50 mg, 0.156 mmol) in CH2Cl2 (0.67 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 4 h and concentrated in vacuo to afford 50.9 mg of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. DIEA (80 μL, 0.454 mmol, 2 equiv) is added to a suspension of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine (50 mg, 0.227 mmol) in THF (0.4 mL), under an argon atmosphere. 4-Ethyl-phenyl-isocyanate (40 μL, 0.250 mmol, 1.1 equiv) is then added. The resulting yellow solution is stirred at rt for 2 h and concentrated in vacuo. The residue is purified by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 98/2). A second purification affords the title compound as a white solid: ES-MS: 367.0 [M+H]+; single peak at tR=8.94 min (System 2); Rf=0.32 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.C1COCC1.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH3:19])=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCNCC1
Yield: 99.9 %

Procedure:
(±)-Phenylmethyl 4-[1-({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)ethyl]-1-piperidinecarboxylate (Example 139, 0.37 g, 0.75 mmol) was dissolved in MeOH (10 mL) and THF (5 mL). 10% of Pd/C (40 mg, Degussa type) was added, and the mixture was placed under an atmosphere of hydrogen using a H2 balloon at ambient temperature for 4 h. The mixture was filtered through Celite® and the filtrate was concentrated to give 0.27 g (100%) of (±)-2-[4-(methylsulfonyl)phenyl]-5-{[1-(4-piperidinyl)ethyl]oxy}pyridine as a viscous colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.9 Hz), 8.12 (d, 2H, J=8.5 Hz), 8.00 (d, 2H, J=8.3 Hz), 7.72 (d, 1H, J=8.8 Hz), 7.30-7.25 (m, 1H), 4.30-4.20 (m, 1H), 3.20-3.10 (m, 2H), 3.08 (s, 3H), 2.70-2.60 (m, 2H), 1.95-1.65 (m, 3H), 1.45-1.25 (m, 5H); LRMS (ESI), m/z 361 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].Cl.Cl.[NH2:18][C@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@H:19]([NH:18][C:12]([C:10]1[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=3[CH:9]=1)=[O:14])[CH2:20]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
187 mg (0.90 mmol) of 5-nitrobenzofuran-2-carboxylic acid, 150 mg (0.75 mmol) of (S)-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90 mmol) of HATU, 350.5 mg (3.71 mmol) of N,N-diisopropylethylamine and 5 ml of DMF are reacted according to the general procedure (variant B). 169.1 mg (70% of theory) of the title compound are obtained. The analytical data correspond to those of the enantiomeric compound from example 30.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(=S)=S>[C:5]([C:16]1[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=1)(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)Cl
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCC(=O)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
104.5g (0.76mol) of anhydrous aluminum chloride and 92.1g (0.76mol) of valeroylchloride were added to 350ml of carbon disulfide chilled at 0° C. To the resulting mixture with chilling and stirring, 100g (0.64mol) of bromobenzene was added and the solution was stirred at room temperature for 24 hours. After completion of the reaction, the resulting mixture was added to 400ml of cold 4N hydrochloric acid and the aluminum chloride complex was decomposed. Then the organic layer was extracted with chloroform and washed with water and the solvent was removed by distillation. The residue was distilled under reduced pressure to yield 95g of 4-pentanoylbromobenzene having a b.p. 105° to 110° C./2mmGn.
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.[NH2:16][CH:17]([CH3:20])[CH2:18][OH:19]>C(OCC)C>[OH:19][CH2:18][CH:17]([NH:16][C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[CH3:20]
Reactant: CC(N)CO
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Solvent: O
Solvent: CCOCC
Product: CC(CO)NC1=NS(=O)(=O)c2cnccc2N1
Reaction time: 3 h

Procedure:
A suspension of 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate and 2-amino-1-propanol (0.75 mL) was refluxed for 90 min (until completion of the reaction; t.l.c.). After cooling, the addition of diethylether (20 mL) gave rise to the separation of an oily residue. After decantation of the etheral solution, the residue was solubilized in methanol (1 mL) and then supplemented with diethylether (15 mL). An oily residue separated again. After decantation of the supernatent, the oily residue was solubilized in acetone (6 mL). A fine precipitate readily appeared. After 3 h at +4° C., the resulting precipitate was collected by filtration, washed with acetone and dried (yield: 0.33 g); m.p. 213°-216° C. (Compound 19).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1c(C(=O)O)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c1) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>CN(C=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 75.4 %

Procedure:
4-fluoro-3-nitro-toluene (346 mg, 2.2 mmol) and imidazole (299 mg, 4.4 mmol) was dissolved in DMF (5 mL) and the reaction heated to 90° C. for 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and 1 M HCl (aq). The aqueous layer was separated and basified with NaOH (s) and extracted with DCM. The DCM was concentrated in vacuo and the residue purified by flash chromatography (Silica, EtOAc:Heptane) to afford the title compound (337 mg, 75%). LC/MS: (00-60% B in A): tR=1.69 min, >90%, m/z (ESI)=204 (MH+).
Reaction SMILES: CN(C=O)C.[C:6]([NH:23][CH2:24][C:25](O)=[O:26])([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7].C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:13]1[CH:12]=[C:11]2[CH:10]([CH2:9][O:8][C:6]([NH:23][CH2:24][CH:25]=[O:26])=[O:7])[C:22]3[C:17]([C:16]2=[CH:15][CH:14]=1)=[CH:18][CH:19]=[CH:20][CH:21]=3
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=CCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Wang resin (70 g, 119 mmol, PL-Wang, Polymer Labs, 1.7 mmol/g.) was swollen in 550 mL of methylene chloride and 100 mL of DMF and stirred for 30 min with an overhead stirrer. 71 g (238 mmol) of FMOC-glycine were added, followed by 60 g (476 mmol) of diisopropylcarbodiimide and 2.4 g (19.7 mmol) of 4-dimethylaminopyridine. The reaction was stirred for 3.5 h at room temperature, the resin was filtered, washed with alternating methanol and methylene chloride and dried in a vacuum oven.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[N:24][CH:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(CCCN)Cc1ncccc1C
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(CCCNC(=O)c1ccc(O)nc1)Cc1ncccc1C
Yield: 13.8 %

Procedure:
Using General Procedure G: To a solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-propane-1,3-diamine (0.24 g, 0.84 mmol) in dry DMF (4 mL) was added 6-hydroxy-nicotinic acid (0.121 g, 0.87 mmol) followed by EDCI (0.182 g, 0.95 mmol), HOBT (0.128 g, 0.95 mmol), and DIPEA (0.25 mL, 1.44 mmol). Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 47 mg (14%) of the free base of the title compound as a colorless oil. Conversion to the HBr salt gave COMPOUND 232 (65 mg, 78%) as a white solid. 1H NMR (D2O) δ 1.74-1.84 (m, 2H), 2.47 (s, 6H), 2.64-2.69 (m, 2H), 3.24 (dd, 2H, 6.3 Hz), 4.31 (s, 4H), 6.62 (d, 1H, J=9.6 Hz), 7.80-7.84 (m, 3H), 7.95 (d, 1H, J=2.1 Hz), 8.32 (d, 2H, J=8.1 Hz), 8.58 (d, 2H, J=6.0 Hz); 13C NMR (D2O) δ 17.24, 25.16, 37.61, 51.91, 53.99, 115.32, 119.34, 126.02, 137.52, 137.87, 138.75, 140.81, 148.48, 150.88, 166.80; ES-MS m/z 406 (M+H). Anal. Calcd. for C23H27N5O2.3.2HBr.3.0H2O: C, 38.45; H, 5.08; N, 9.75; Br, 35.59. Found: C, 38.32; H, 4.94; N, 9.48; Br, 35.96.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:4]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CC(N(C)C)=O>[N:15]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:4]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)COc1cccc(CCl)n1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: [N-]=[N+]=NCc1cccc(OCC(F)(F)F)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 122.3 %

Procedure:
A mixture of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.35 g, 1.55 mmol, Step-4) and sodium azide (0.20 g, 3.10 mmol) in DMA (8 mL) is stirred 90° C. for 1 hour. The reaction mixture is poured into water (50 mL), and extracted with n-hexane/EtOAc (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.44 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-6) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6](Cl)[C:3]=1[CH:4]=O.[NH2:12][NH2:13]>O1CCOCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]2[C:3]=1[CH:4]=[N:12][NH:13]2
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Reactant: NN
Solvent: C1COCCO1
Product: Clc1cc(Cl)c2cn[nH]c2c1
Temperature: 160 °C
Yield: 38.6 %

Procedure:
In a microwave vial 2,4,6-trichlorobenzaldehyde (4.0 g, 19.1 mmol) was dissolved in 1,4-dioxane (8 mL) and hydrazine (7.2 mL, 229 mmol) was added. The vial was sealed and heated under microwave irradiation at 160° C. for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to provide 1.38 g (38%) of 4,6-dichloro-1H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.14 (s, 1H), 7.44 (s, 1H), 7.20 (d, J=1.5 Hz, 15H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:18].[O-]S([O-])(=O)=O.[Ca+2].[CH3:25]I>>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:8][CH2:9][CH:10]([O:13][CH3:25])[CH2:11][CH2:12]1)[CH2:6][C:5]2=[O:18]
Reactant: O=C1CC2(CCC(O)CC2)Oc2ccc(Br)cc21
Reactant: CI
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: COC1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 20 mL vial was placed 6-bromo-4′-hydroxyspiro[chroman-2,1′-cyclohexan]-4-one (46 mg, 0.148 mmol) and it was azeotroped with acetonitrile (3 mL). The solid was dissolved in acetonitrile (1 mL). To this heterogenous solution was added Ag2O (103 mg, 0.444 mmol) followed by freshly grounded Drierite (160 mg). Then MeI (185 μL, 2.97 mmol) was added, the vial was capped and the reaction was allowed to stir at room temperature. After 2 days stirring the alcohol was totally consumed. The reaction mixture was filtered through a plug of Celite and the cake was rinsed with ethyl acetate three times (2 mL/each). The filtrate was concentrated yielding crude 6-bromo-4′-methoxyspiro[chroman-2,1′-cyclohexan]-4-one (48 mg, 0.148 mmol, 100% yield) which by 1H NMR looked>90% pure.
Reaction SMILES: [NH2:1]CC(O)=O.[CH2:6]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][CH:13]=1)[CH3:7].N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH3:19][O:18][C:16](=[O:17])[CH2:15][N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:6][CH3:7])[CH:9]=1)[NH2:1]
Reactant: CCc1cccc(NCC(=O)OC)c1
Reactant: NCC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cccc(N(N)CC(=O)OC)c1
Reaction time: 2 h
Yield: 14 %

Procedure:
To the glycine (Intermediate 38; 35 g; 0.181 mol) in acetic acid (50 ml) at -5° C. was added, dropwise, a solution of sodium nitrite (13.75 g; 0.199 mol) in H2O (10 ml). The temperature of the reaction mixture was not allowed to rise above 0°. After stirring for a further 2 h, zinc dust (26.02 g, 0.398 mol) was added portionwise, once again so as not to allow the temperature of the reaction mixture to rise above 0°. After 5 h, a further quantity of zinc dust (13.01 g, 0.199 mol) was added and the mixture was stirred overnight. The excess zinc dust was removed by filtration through celite. The reaction mixture was then quenched with sodium bicarbonate solution. Extraction into ethyl acetate followed by washing with water, brine and finally drying (over Na2SO4) gave the crude title compound (ca. 35 g). This crude material was chromatographed using Ethyl acetate: Petroleum ether (1:3) to yield Intermediate 39 (5.21 g; 14%) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:28]=[CH:27][C:12]([S:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1>ClCCl>[Br:8][C:9]1[CH:28]=[CH:27][C:12]([S:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(Br)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(SC2CCNCC2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (7.5 ml) was added in portions to a stirred, ice-cooled solution of 4-(4-bromothiophenoxy)-1-t-butoxycarbonylpiperidine (2.6 g) in dry dichloromethane (5 ml) under an atmosphere of argon so that the temperature of the mixture was maintained between 5 and 10° C. The solution was stirred at 5° C. for 1 hour, then at ambient temperature for 2 hours. The solution was evaporated. The residual oil was treated with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate (3×70 ml). The ethyl acetate extracts were combined, dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica gel, using a mixture of 95:5:3, ethyl acetate:methanol:aqueous ammonia (density 0.88 g/cm3) as eluent, to give 4-(4-bromothiophenoxy)piperidine (1.9 g) as an off-white solid;
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:11]2[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([CH2:28][Cl:27])=[CH:30][CH:31]=3)[CH:10]=2)=[O:26])=[CH:19][CH:20]=1)#[N:25]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Triethylamine (0.55 ml) was added to a suspension of N-(3-amino-4-methylphenyl)-4-cyanobenzamide (0.40 g), 4-(chloromethyl)benzoyl chloride (0.45 g) and 4-dimethylaminopyridine (0.019 g) in methylene chloride (12 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated with water. The resultant solid was isolated and washed in turn with 2N hydrochloric acid and a saturated aqueous sodium bicarbonate solution. The solid was dried under vacuum at 55° C. to give the required starting material (0.64 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 4.82 (s, 2H), 7.23 (d, 1H), 7.58 (m, 3H), 7.84 (s, 1H), 7.99 (m, 4H), 8.1 (d, 2H), 9.91 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M−H− 402.