Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-])=O>[Fe].CC(O)=O>[NH2:1][C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[S:12][CH:13]=[CH:14][N:15]=1
Reactant: N#Cc1csc([N+](=O)[O-])c1-c1nccs1
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1csc(N)c1-c1nccs1
Temperature: 60 °C

Procedure:
A 30 mL reaction vial was charged with 5-nitro-4-(thiazol-2-yl)thiophene-3-carbonitrile (180 mg, 0.76 mmol) and AcOH (3 mL). A spatula tip of iron dust was added and the reaction vial was heated to 60° C. for 20 min. The reaction mixture was cooled to 23° C. and partitioned between methylene chloride and sodium bicarbonate solution. The organic solution was dried over sodium sulfate and concentrated to give 5-amino-4-(thiazol-2-yl)thiophene-3-carbonitrile as a red solid. LCMS showed an m/z of 208.0 with a retention time of 2.016 min using method [1].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Br[CH2:20][C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:14]([O:13][C:12]([NH:11][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH2:6]2)=[CH:10][C:2]=1[O:1][CH2:20][C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:25][CH:26]=1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1cnc(CBr)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cc1O)CCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(COc2cc3c(cc2NC(=O)OC(C)(C)C)CCC3)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
1.00 g of tert-butyl (6-hydroxy-2,3-dihydro-1H-inden-5-yl)carbamate was dissolved in 10.0 mL of DMF, and 1.08 g of ethyl 5-(bromomethyl)pyrazine-2-carboxylate and 721 mg of potassium carbonate were added thereto, followed by stirring at 60° C. for 1 hour. The reaction liquid was poured into a 5% w/v aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a 5% w/v aqueous citric acid solution, water, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to obtain 690 mg of ethyl 5-[({6-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}oxy)methyl]pyrazine-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=O)[CH:6]=[C:5]2[CH3:14].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([Cl:19])[CH:6]=[C:5]2[CH3:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]c2c(C)cc(Br)cc12
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Cl)nc2c(C)cc(Br)cc12
Yield: 93 %

Procedure:
This quinolone (410 mg, 1.6 mmol) in POCl3 (5 mL) was refluxed for 2 h, then poured onto ice. The solution was neutralized to pH 7 by addition of NH4OH, and the resulting solid collected by filtration. Washing with water and drying in vacuo gave 6-bromo-2-chloro-4,8-dimethyl-quinoline (407 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:10][C:9](=[O:11])[C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)([CH3:13])[CH3:12])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)(OCc1ccc(F)cc1)C(=O)O
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)OCc3ccc(F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 770 mg of 2-(4-fluorobenzyloxy)-2-methylpropionic acid and 1.0 gof (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.17 g of the title compound as a colorless foam.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[CH:2][C:1]([CH:4]1[C:9]([OH:10])=[C:8]([C:11](=[O:13])[CH3:12])[C:7](=[O:14])[O:6][C:5]1=[O:15])=[O:3])(=[O:18])[CH3:17]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CC(=O)Nc1cccc(C=O)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)c1

Procedure:
Similarly, 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 3.2 g. (0.02 m.) of m-acetamidobenzaldehyde, 200 ml. of chloroform and 0.5 ml. of piperidine is azeotroped for four hours and the reaction mixture is filtered to yield 3-(m-acetamidocinnamoyl)-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 222°-224° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:12][N:13]([CH:15]=O)[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](/[CH:8]=[CH:12]/[N:13]([CH3:15])[CH3:14])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Product: CN(C)/C=C/c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 5-bromo-2-methyl-3-nitropyridine (3.0 g, 13.8 mmol) and N—N-dimethylformamide-dimethylacetal (DMF-DMA) in 45 ml of DMF was heated at 90° C. for 4 hours, and cooled to room temperature. The solvent was evaporated and the residue dissolved in dichloromethane (DCM), which was washed with saturated NaHCO3 and brine, and chromatographed (EtOAc/Hexanes 1:10) to give a red solid, 2.86 g, in 76% yield.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:16])[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:3])[CH3:2].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:16])[C@@H:11]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Product: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxo-4-methylpentyl)-2-oxazolidinone (5.17 g), prepared in Referential Example 38, and tert-butyl bromoacetate (18.5 ml) as starting materials, the desired compound (6.16 g), having a m.p. of 143°-144° C. after recrystallization from aqueous methanol, was obtained.
Reaction SMILES: C(OC1C=CC(C=O)=CC=1)(C)C.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.COC(=O)[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1>>[N:23]1[CH:22]=[CH:27][CH:26]=[C:25]([O:28][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:24]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: BrC1=NOCC1
Agent: CC(C)Oc1ccc(C=O)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-140a and I-140b were prepared in 4 steps from 4-iso-propoxybenzaldehyde using Method 8 followed by cycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using Method 5 followed by hydrolysis using the analogous conditions as in Example 94 These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=343.5 m/z. Activity: A
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:16]O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+]>CCO.[Ni]>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(C=NO)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reaction time: 4 h

Procedure:
To a solution of [3-(hydroxyimino-methyl)-phenoxy]-acetic acid tert-butyl ester (2.25 g, 5.96 mmol) in EtOH (10 mL) was added Raney Nickel (about 1 g, washed with water followed by EtOH) in 100 mL ethanol. Additional EtOH (90 mL) was required for the transfer. Ammonium hydroxide (10 mL) was added and the mixture was shaken under 45 psi of H2 for 4 hours. The catalyst was removed via filtration through Celite® (diatomaceous earth) and the solution was concentrated to a clear oil. Purification via flash chromatography on silica gel (96.5/3.5/0.1 to 9/1/0.1 CH2Cl2/MeOH/NH4OH) afforded the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 6.92 (m, 2H), 6.72 (d, 1H), 4.50 (s, 2H), 3.82 (s, 2H), 1.96 (m, 2H), 1.46 (s, 9H); MS 238 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+].C>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([N:19]2[CH2:20][CH2:21][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=3)[CH2:17][CH2:18]2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(N2CCN(c3ccccn3)CC2)cc1F
Temperature: 142.5 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
2-Fluoro-4-iodoaniline (750 mg, 3.16 mmol) was added to a suspension of 2-pyridyl-piperazine (568 mg, 3.48 mmol), 8-hydroxyquinoline (68 mg, 0.47 mmol) and potassium carbonate (660 mg, 4.74 mmol) in dimethylsulfoxide (5 mL) under an inert atmosphere. Cuprous iodide (94 mg, 0.47 mmol) was added and the reaction mixture was heated at 140-145° C. for 16 h. The reaction mixture was allowed to cool to ambient temperature and poured into a mixture of ammonium hydroxide, ethyl acetate and charcoal and stirred for 30 min. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulphate and concentrated to dryness in vacuo. The crude product was purified by column chromatography with silica gel (100-200 mesh) using 13% ethyl acetate in petroleum ether as eluent to afford 2-fluoro-4-[4-(2-pyridyl)piperazin-1-yl]aniline (220 mg, 26%) as an orange semi-solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[C:26]([N:28]([CH3:30])[CH3:29])=[O:27]>>[CH3:30][N:28]([CH3:29])[C:26](=[O:27])[C:25]1[CH:31]=[CH:32][CH:33]=[C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)[CH:24]=1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: CN(C)C(=O)c1cccc(CCl)c1
Product: CN(C)C(=O)c1cccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-chloromethyl-N,N-dimethyl-benzamide [CAS 442910-26-1]. MS (ES+) 436.3
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Li+].[OH-].CCOC(C)=O.Cl>CO.O>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccn(-c2ccccc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cccn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A mixture of methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (70 mg, 0.31 mmol) and LiOH (40 mg) in methanol (6 mL) and water (1 mL) was stirred at rt overnight. To the reaction mixture were added EtOAc (50 mL) and 1 N aq HCl (15 mL), EtOAc layer was separated, dried over MgSO4, and concentrated in vacuo to obtain the acid (55 mg, 83%) as a light yellow solid. 1H NMR (DMF-d7) δ 11.77 (br s, 1H), 8.57 (dd, 1H, J=7.4, 2.0 Hz), 8.26 (dd, 1H, J=6.6, 1.6 Hz ), 7.64-7.55 (m, 5H), 6.88 (t, 1H, J=7.0 Hz); MS(ESI+) m/z 216.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH:20]1([CH2:23][NH:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[CH:14]4)=[O:9])[CH:3]=2)[CH2:22][CH2:21]1
Reactant: COCCNCC1CC1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Product: COCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and N-(cyclopropylmethyl)-2-methoxyethanamine, the title compound was obtained as a beige solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:21]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)=[O:22])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Subject 4.0 g. (29.0 mmoles) of p-methoxy-benzylamine, 5.7 g. (29.0 mmoles) of adamantane carboxylic acid chloride and 10 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from chloroform to obtain the product of this Example, m.p. 91°-94° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[C:5]([N:24]=O)=[C:4]([NH2:26])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC=CC=1C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])=[CH:14][CH:15]=2)[C:5]([NH2:24])=[C:4]([NH2:26])[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Nc1nc(N)c(N)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
2,6-Diamino-5-nitroso-4-[4-(2,2,2-trifluoro-acetylamino-methyl)-benzyloxy]-pyrimidine (1.22 g, 3.3 mmol) and triphenylphosphine (1.89 g, 7 mmol) in 20 mL o-xylene are heated to reflux for 1 h. After cooling to room temperature the solvent is removed in vacuo and the remaining residue redissolved in methanol. The residue is adsorbed on SiO2 and purified by flash column chromatography (CH2Cl2/methanol 95:5 to 5:1) to yield the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)[CH3:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([NH:2][CH2:3][CH:4]([N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)[CH3:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CC(CN)n1nnnc1S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(CNC(=O)OC(C)(C)C)n1nnnc1S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 1-[1-(aminomethyl)ethyl]-1H-tetrazole-5-thiol hydrochloride (17 g) and triethylamine (19.33 g) in 50% aqueous dioxane (80 ml) was added a solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (21.4 g) in dioxane (50 ml) under cooling in an ice bath. The mixture was stirred for 1.5 hours at ambient temperature and concentrated to third volume. The aqueous solution was washed with diethyl ether and the washings were reextracted with aqueous solution of potassium carbonate. The two aqueous solutions were combined, washed with diethyl ether and mixed with ethyl acetate. The mixture was acidified with 10% hydrochloric acid and the organic layer was separated out. The solution was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with n-hexane to give 1-[1-{(N-t-butoxycarbonylamino)methyl}ethyl]-1H-tetrazole-5-thiol (19.15 g), mp 156° to 158° C.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1>C1C=CC=CC=1>[C:2](=[C:3]1[CH2:4][C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]1=[O:1])([CH3:12])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: c1ccccc1
Product: CC(C)=C1Cc2ccccc2C1=O

Procedure:
The reaction mixture was dissolved in 300 ml of benzene and 4.2 g of p-toluenesulfonic acid monohydrate was added to the solution and refluxed for 2 hours for component distillation. The product was used in the subsequent reaction without purification.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]#[C:13][Si](C)(C)C)[CH:9]=[CH:10][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CO.O.CCOC(C)=O>[F:1][CH:2]([F:18])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cccc(OCCC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C#Cc1cccc(OCCC(F)F)c1
Reaction time: 1.5 h

Procedure:
To a solution of ((3-(3,3-difluoropropoxy)phenyl)ethynyl)trimethylsilane (2.1 g, 7.82 mmol) from the previous step in MeOH (19.5 mL) was added K2CO3 (10.81 g, 78.2 mmol) at room temperature. The reaction mixture was stirred for 1.5 h after which it was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc once. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oil. The oil was absorbed onto Celite (8 g). Flash chromatography (SiO2, 1% EtOAc 99% Hexanes to 3% EtOAc 97% Hexanes) provided 1.31 g, 85%, of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)[C:27]=1[C:28]([OH:30])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:28]([C:27]1[C:31]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[CH:32][CH:33]=[CH:34][C:26]=1[F:25])=[O:30]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
Reaction SMILES: [N:1]([C@@H:4]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH3:20])[C:5](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].[OH2:28].OO.[OH-].[Li+]>C1COCC1>[N:1]([C@@H:4]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH3:20])[C:5]([OH:6])=[O:28])=[N+:2]=[N-:3]
Reactant: O
Reactant: C[C@@H](c1ccc(Br)cc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)[C@H](N=[N+]=[N-])C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of the product from Step D (2.77 g, 6.23 mmol) in THF (60 mL) was added water (20 mL). The solution was stirred at 0° C. for 15 min, and then 30% hydrogen peroxide (6.0 mL, 52.9 mmol) was added followed by slow addition of lithium hydroxide (0.50 g, 21.2 mmol). The resultant mixture was stirred at 0° C. for 4 h. The reaction was quenched by addition of saturated aqueous sodium sulfite solution and stirred at room temperature for 30 min. The aqueous phase was separated and washed with three portions of dichloromethane. The aqueous phase was then acidified to pH 1 with 3N hydrochloric acid and extracted with three portions of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated in vacuo to give the product, which was used in the next step directly.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][NH:14][CH2:15][CH2:16][C:17]#[N:18].O>CN(C)C=O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:14]([CH2:15][CH2:16][C:17]#[N:18])[CH3:13])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CNCCC#N
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCC#N)C(=O)c1ccccc1N
Reaction time: 6 h

Procedure:
To Isatoic Anhydride (4.60 g, 28.2 mmol) in N,N-Dimethylformamide (30 mL) was added 3-Methylamino-propionitrile (3.00 mL, 32.1 mmol) and the reaction was stirred under an atmosphere of Nitrogen. After 6 h, the mixture was poured into 200 mL water, then extracted 3×100 mL DCM, washed with 100 mL satd. sodium bicarbonate, which was back extracted with 50 mL DCM. The combined organics were washed with brine (100 mL) and dried over sodium sulfate, then conc. in vacuo afforded 2-Amino-N-(2-cyano-ethyl)-N-methyl-benzamide as an oil in quantitative yield. 1H-NMR: 7.18 (dd, 1H, J=9.0, 9.0 Hz), 7.13 (d, 1H, J=7.3 Hz), 6.74 (m, 2H), 4.31 (br s, 2H), 3.76 (t, 2H, J=6.6 Hz), 3.15 (s, 3H), 2.75 (t, 2H, J=6.6 Hz).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>O1CCOCC1.O.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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])=[C:24]([Cl:23])[CH:25]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: O=C(c1ccc(B(O)O)cc1Cl)N1CCOCC1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3ccc(C(=O)N4CCOCC4)c(Cl)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 22.8 %

Procedure:
Cs2CO3 (682 mg, 2.10 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (3-chloro-4-(morpholine-4-carbonyl)phenyl)boronic acid (229 mg, 0.85 mmol) in dioxane: water (7 mL: 3 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (40 mg, 0.035 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 70-80% ethyl acetate in pet-ether to afford 68 mg (Yield: 22.5%) of the title compound as a pale yellow solid. Product was converted to its HCl salt by using HCl in ether (2M) to afford 60 mg of the HCl salt of the title compound as a pale yellow solid.