Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1N=CC(N2CCC([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)CC2)=CC=1.[CH3:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[CH3:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][CH:47]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=4)[CH2:16]3)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1
Reactant: Cc1cccc(N2CCC(=O)CC2)c1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: Cc1cccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby 1-(3-methylphenyl)piperidin-4-one was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.77-1.87 (m, 2H), 2.04-2.19 (m, 3H), 2.40-2.47 (m, 1H), 2.74 (t, J=12.7 Hz, 2H), 3.16-3.24 (m, 1H), 3.34-3.42 (r, 2H), 3.54-3.63 (m, 2H), 3.77 (t, J=12.9 Hz, 2H), 4.03 (s, 2H), 4.48-4.52 (m, 1H), 6.68 (d, J=7.5 Hz, 1H), 6.75-6.80 (m, 2H), 7.10 (t, J=7.9 Hz, 1H), 7.11 (t, J=7.9 Hz, 1H), 7.69 (t, J=7.9 Hz, 2H), 7.87 (d, J=8.1 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.22 (s, 1H), 8.36 (s, 1H). MS m/z: 489 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].[Se](=O)=[O:57]>C(O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:57])[CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: O=[Se]=O
Solvent: CCO
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 70 °C
Yield: 68.5 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (735 mg) in 95% ethanol (10 ml) was added 130 mg of selenium dioxide. The flask was fitted with a water condenser and heated to 70° C. on a mantle. After 45 hours the mixture was cooled to room temperature, filtered through diatomaceous earth and the filtrate poured into a saturated sodium bicarbonate solution. This was extracted with ethyl acetate, and the organic phase was washed with brine and dried over magnesium sulfate. The solution was concentrated and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) to give the title compound (514 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])CBr)=[CH:4][CH:3]=1.C([N:14](CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH:14]1[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=2)[CH:8]=[CH:11]1
Reactant: CCN(CC)CC
Reactant: CC(CBr)c1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.6 %

Procedure:
A mixture of Intermediate 3 (0.31 g, 1.0 mmol), 2-(4-fluorophenyl)propyl bromide (0.228 g, 1.05 mmol), triethylamine (0.202 g, 2.0 mmol) and sodium iodide (0.165 g, 1.1 mmol), in DMF (20 ml) was heated at 90° C., with stirring, for 16 h. The mixture was cooled to room temperature and partitioned between dichloromethane and water. The CH2Cl2 layer was separated, dried (Na2SO4) and evaporated under vacuum. The crude product was chromatographed through silica gel eluting with CH2Cl2 /MeOH/NH3 (90:10:1) to give the title-indole (0.125 g, 28%). The 3.0 hydrogen oxalate monohydrate salt was prepared, mp 203-205° C., (Found: C, 52.11; H, 5.60; N, 11.45. C26H31N6F. 3.0 (C2H2O4) 1.0H2O requires C, 52.31; H, 5.35; N, 11.44%), δ(360 MHz, D6 -DMSO) 1.17 (3H, d, J=6.8 Hz, Me), 1.92-2.06 (2H, m, CH2), 2.44-3.26 (15H, m, 7 of CH2 and CH), 7.08-7.13 (2H, m, Ar--H), 7.26-7.33 (4H, m, Ar--H), 7.50 (1H, d, J=8.6 Hz, Ar--H), 7.78 (1H, d, J=1.5 Hz, Ar--H), 9.01 (2H, s, Ar--H), 11.16 (1H, s, NH).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:36][CH2:37][OH:38].C(OCC)(=O)C>C(#N)C>[CH2:23]([C@@H:19]1[N:20]([CH2:36][CH2:37][OH:38])[CH2:21][CH2:22][N:17]([C:15]2[N:16]=[C:11]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[NH:4][N:3]=[C:2]4[CH3:1])[N:12]=[N:13][CH:14]=2)[CH2:18]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1n[nH]c2ccc(-c3nncc(N4CCN[C@@H](Cc5ccccc5)C4)n3)cc12
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ccc(-c3nncc(N4CCN(CCO)[C@@H](Cc5ccccc5)C4)n3)cc12
Yield: 7.3 %

Procedure:
To a solution of 5-[(S)-3-benzylpiperazin-1-yl]-3-(3-methylindazol-5-yl)-[1,2,4]triazine 12 (28.5 mg, 0.074 mmol.) in acetonitrile (2 mL) was added sodium bicarbonate (6.2 mg, 0.074 mmol.) and 2-bromoethanol (9.2 mg, 0.11 mmol.). The reaction mixture was heated under gentle reflux overnight. Ethyl acetate (50 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 5-[(S)-3-benzyl-4-hydroxyethyl-piperazin-1-yl]-3-(3-methylindazol-5-yl)-[1,2,4]triazine 60 (2.3 mg, 0.0054 mmol.).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH:21]([CH3:23])[CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:23])[CH3:22]
Reactant: CC(C)Sc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 10.6 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-isopropylthiopyridine (1.40 g, 7.9 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (0.24 g, 10%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:17](=[O:18])[N:16]2[CH2:19][C@@H:20]([O:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:21][C@H:15]2[C:14](=[O:33])[NH:13][C@:12]2([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:34][C@H:11]2[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH2:47]([C@@H:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[O:57][C:58](ON1C(=O)CCC1=O)=[O:59])[CH2:48][CH2:49][CH:50]=[CH2:51].Cl>CC#N.CCOC(C)=O>[Br:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([O:22][C@@H:20]2[CH2:19][N:16]3[C:17](=[O:18])[C@@H:3]([NH:2][C:58]([O:57][C@@H:53]4[CH2:54][CH2:55][CH2:56][C@H:52]4[CH2:47][CH2:48][CH2:49][CH:50]=[CH2:51])=[O:59])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][C@@H:11]4[CH2:34][C@@:12]4([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:13][C:14](=[O:33])[C@@H:15]3[CH2:21]2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](N)C(=O)N1C[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Reactant: C=CCCC[C@@H]1CCC[C@H]1OC(=O)ON1C(=O)CCC1=O
Agent: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)OCC)NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccc(Br)cc3)CN2C1=O
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](N)C(=O)N1C[C@@H](OS(=O)(=O)c3ccc(Br)cc3)C[C@H]1C(=O)N2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)OCC)NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccc(Br)cc3)CN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound from Step 1 (300 mg, 0.46 mmol) in MeCN (0.5 mL) was added Et3N (0.19 mL, 1.36 mmol). A solution of the compound from Step 2 (150 mg, 0.51 mmol) in MeCN (1.5 mL) was added, and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was worked up with EtOAc and 1M HCl, and the organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (gradient elution 0 to 100% EtOAc in hexane). LCMS (M+H)+=792.0.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Br[C:8]1[S:9][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1>[Pd]>[CH3:1][C:2]([OH:6])([CH3:3])[C:4]#[C:5][C:8]1[S:9][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:11][CH:12]=1
Reactant: Brc1ccc(C#Cc2ccncc2)s1
Reactant: C#CC(C)(C)O
Agent: [Pd]
Product: CC(C)(O)C#Cc1ccc(C#Cc2ccncc2)s1

Procedure:
The 2-ethynyl-5-(4-pyridyl)ethynyl thiophene is synthesized by the reaction sequence shown below. In the first step, bromination of 1-(2-thienyl)-2-(4-pyridyl)ethene followed by base-catalyzed dehydrohalogenation gives 2-bromo-5-{2-(4-pyridyl)ethynyl}thiophene (I): ##STR5## In the second step, the palladium catalyzed addition of 2-methyl-3-butyn-2-ol to compound I gives 2-{3-methyl-3-hydroxybutynyl}-5-{2-(4-pyridyl)ethynyl}thiophene (II): ##STR6## The term "Ph" in the palladium catalyst formula means "phenyl". In the third step, removal of the protecting group using KOH in methanol gives the acetylene-terminated thermoset monomer 2-ethynyl-5-(4-pyridyl)ethynyl thiophene (III): ##STR7##
Reaction SMILES: P([O-])([O-])([O-])=O.CC1(C)N([O])C(C)(C)CCC1.[Br:17][C:18]1[C:19]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[CH:20][C:21]([CH2:24][OH:25])=[N:22][CH:23]=1.Cl[O-:32].[Na+].[OH-].[Na+].Cl>C(#N)C.O>[Br:17][C:18]1[C:19]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[CH:20][C:21]([C:24]([OH:32])=[O:25])=[N:22][CH:23]=1
Reactant: OCc1cc(OCC2CC2)c(Br)cn1
Reactant: [O-]Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cc(OCC2CC2)c(Br)cn1
Temperature: 35 °C
Yield: 1374.2 %

Procedure:
Aqueous phosphate buffer (6.7 mL, pH=6.7) and 2,2,6,6-tetramethylpiperidine 1-oxyl (17 mg, 81 μmol) were added to a solution of (5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)methanol (300 mg, 1.16 mmol) in acetonitrile (6 mL). The mixture was warmed to 35° C. Water (4.6 mL) and a solution of sodium hypochlorite (17 mg, 14 μL, 23 μmol) in water (2.3 mL) were added within 2 h. After 20 h the mixture was cooled to ambient temperature, water (40 mL) and 2N aqueous NaOH solution (8 mL) were added. The mixture was poured onto an ice cold aqueous Na2SO3 solution (1.6 g Na2SO3 in 30 mL of water), acidified with 2N aqueous HCl solution and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (86 mg, 27%) as off-white solid which was used in the next step without further purification; MS (ESI, m/z): 271.9 (MH−).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>CCCCCC>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([O-:29])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCNc1ccccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 17.5 h
Yield: 97.8 %

Procedure:
Octadecylamine (11.858 g) was added to 2-chloronitrobenzene (3.151 g) and the mixture was stirred for 17.5 hours at 125° C. After n-hexane was added to the reaction mixture, solid materials were crushed well and removed out by filtration. The filtrate was concentrated and the residue (9.13 g) was purified by silica gel column chromatography (silica gel 90 g, n-hexane:ethyl acetate=50:1), thereby yielding the entitled compound (7.642 g) as yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.C1COCC1.C([Li])CCC.Cl[P:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:34]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(Br)=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1)P(c1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
Into a reactor were introduced 3.0 g (8.3 mmol) of the 1,1-bis(4-dimethylaminophenyl)-2-bromopropene and 10 mL of THF under a nitrogen atmosphere. The contents were cooled to −60° C. Thereto was gradually added dropwise 5.2 mL (8.3 mmol; 1.6 M hexane solution) of butyllithium. The resultant mixture was stirred for 30 minutes. Thereafter, 1.1 mL (6.0 mmol) of chlorodiphenylphosphine was added thereto and this mixture was heated to room temperature and stirred for 16 hours. Water was added to the reaction mixture. The resultant mixture was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized twice from hexane/ethanol to obtain 1.9 g (60%) of the target compound as white crystals.
Reaction SMILES: C(S([CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31](=[O:33])[CH3:32])[S:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:34])[CH2:6]1)=O)C.C(Cl)(=O)C([Cl:38])=O>C(Cl)Cl>[Cl:38][CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31](=[O:33])[CH3:32])[S:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:34])[CH2:6]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1S(=O)CC
Solvent: ClCCl
Product: CCOCCSC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl

Procedure:
A solution of 1.2 g p-nitrobenzyl 2-(4-ethylsulfinyl-2-oxo-1-azetidinyl)-3-acetylthio-3-(2-ethoxyethylthio)-acrylate in 50 ml methylene chloride was cooled to -50° C. under a nitrogen atmosphere. Oxalyl chloride (0.196 ml) was added dropwise at -50° C., then the reaction mixture was allowed to warm to -15°. After 1 hour at -15° C. the methylene chloride solution was washed with 20 ml saturated aqueous sodium bicarbonate solution and 20 ml water, dried over anhydrous sodium sulfate and concentratedd in vacuo to an oil (1.2 g). The crude title compound was used without further purification. The NMR spectrum of a deuterochloroform solution showed peaks at 1.23(, 3H); 2.3-3.72(c, 11H); 5.23 (m, 2H); 5.7-6.32(c, 1H); 7.52(m, 2H); and 8.2(m, 2H) ppm. The infrared spectrum of a chloroform solution had absorption bands at 5.6 and 5.78 microns.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.I[C:44]1[C:45]2[C:46](=[CH:50][N:51]([CH2:53][CH2:54][CH2:55][O:56]C3CCCCO3)[N:52]=2)[N:47]=[CH:48][CH:49]=1.[F:63][C:64]1[C:65]([C:71]2[CH:76]=[C:75]([NH2:77])[C:74]([CH3:78])=[CH:73][N:72]=2)=[N:66][C:67]([CH3:70])=[CH:68][CH:69]=1.CC([O-])(C)C.[Na+].Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:63][C:64]1[C:65]([C:71]2[CH:76]=[C:75]([NH:77][C:44]3[C:45]4[C:46](=[CH:50][N:51]([CH2:53][CH2:54][CH2:55][OH:56])[N:52]=4)[N:47]=[CH:48][CH:49]=3)[C:74]([CH3:78])=[CH:73][N:72]=2)=[N:66][C:67]([CH3:70])=[CH:68][CH:69]=1
Reactant: Ic1ccnc2cn(CCCOC3CCCCO3)nc12
Reactant: Cc1ccc(F)c(-c2cc(N)c(C)cn2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(CCCO)nc34)c(C)cn2)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.74 mg, 6.46 μmol), 7-iodo-2-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2H-pyrazolo[4,3-b]pyridine (100 mg, 0.258 mmol), Pd2(dba)3 (5.91 mg, 6.46 μmol), 3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-amine (56.1 mg, 0.258 mmol) and sodium 2-methylpropan-2-olate (74.5 mg, 0.775 mmol) were combined in dioxane (5 mL) and heated at 120° C. for 1 hour. The reaction was then cooled, concentrated, and purified by prep-HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 10-50% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give a residue which was combined with 1N HCl (4 mL) and stirred at room temperature for 1 hour before the solvent was removed to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.14 (t, J=6.19 Hz, 2H) 2.68 (s, 3H) 2.71 (s, 3H) 3.52 (t, J=5.94 Hz, 2H) 4.68 (t, J=6.95 Hz, 2H) 7.54 (d, J=6.57 Hz, 1H) 7.64 (dd, J=8.59, 3.54 Hz, 1H) 7.82 (dd, J=11.37, 8.59 Hz, 1H) 8.53 (s, 1H) 8.71 (d, J=6.57 Hz, 1H) 8.86 (s, 1H) 8.90 (s, 1H). MS [M+H] found 393.4.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][C:26]([F:29])([F:28])[C:25]([F:31])([F:30])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][C:26]([F:28])([F:29])[C:25]([F:30])([F:31])[CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2nnc3c(N4CC(F)(F)C(F)(F)C4)nc(C(C)(C)C)nc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Temperature: 70 °C

Procedure:
The crude 5-tert-Butyl-3-(4-methoxy-benzyl)-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine was treated with triethylsilane in TFA and heated to 70° C. for 20 h and evaporated. The crude material was used without further purification in the consecutive step.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:8]([CH3:9])[C:7]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=3[F:29])[CH:11]=2)=[N:6][CH:5]=1.Cl>CC(C)=O.O>[F:29][C:21]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=1[O:19][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:11]=[C:10]([C:7]3[N:8]([CH3:9])[C:4]([CH:3]=[O:2])=[CH:5][N:6]=3)[S:18][C:17]=12
Reactant: COC(OC)c1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cn1c(C=O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution 42 (1.8 g, 4.05 mmol) in acetone (100 mL) and water (100 mL) was added diluted HCl (20 mL, 2M, 40.0 mmol) and the reaction mixture was stirred at RT overnight. It was then concentrated to dryness. The residual solid was dissolved in DCM, washed with water, dried over Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to afford 43 (1.3 g, 81% yield), which used without additional purification. MS (m/z): 399.2 (M+H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:18])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1

Procedure:
Heated at reflux for 2 hrs., a solution of 25 g (0.13 mole) of 4-biphenylcarboxylic acid, in 125 ml of thionyl chloride. Distilled to remove the excess thionyl chloride, then added 150 ml of AR toluene. Evaporated in vacuo to give a brown solid, 27 g, m.p. softens 107°, some melts 109°-112°, darkens 370°, melts >400°.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([NH:13][NH:14][C:15](=[S:17])[NH2:16])=O)=[C:9]([F:20])[CH:8]=1.N.O>C(O)(=O)CCCC>[Br:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]2[S:17][C:15]([NH2:16])=[N:14][N:13]=2)=[C:9]([F:20])[CH:8]=1
Reactant: NC(=S)NNC(=O)c1ccc(Br)cc1F
Agent: N
Agent: O=S(=O)(O)O
Solvent: CCCCC(=O)O
Solvent: O
Product: Nc1nnc(-c2ccc(Br)cc2F)s1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
H2SO4 (2 mL) was added to a solution of 2-(4-bromo-2-fluorobenzoyl)-hydrazinecarbothioamide (2.9 g, 10.0 mmol) in pentanoic acid (5 mL) and the resulting mixture was stirred at 110° Celsius for 2 hours. After cooling to rt, the reaction mixture was poured into ice-water (20 mL) and treated with NH3.H2O (15 mL). 5-(4-Bromo-2-fluorophenyl)-1,3,4-thiadiazol-2-amine was then isolated via vacuum filtration and air dried. MS (ESI): mass calcd. for C8H5BFN3OS, 272.94, m/z found, 274.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[CH:20][CH:21]=2)[C:7]([C:11]([F:14])([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(C)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)(F)F)cc1N
Temperature: 90 °C
Reaction time: 72 h
Yield: 62.1 %

Procedure:
To a solution of 2-amino-4-(1,1-difluoro-ethyl)-5-iodo-benzoic acid methyl ester (0.80 g, 2.35 mmol) in dioxane (10 mL) were added 1-methyl-5-tributylstannanyl-1H-pyrazole (1.05 g, 2.81 mmol) and Pd(PPh3)2Cl2 (168 mg, 0.235 mmol) and the resulting mixture was stirred at 90° C. for 72 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:10 to 3:7)) to give 2-amino-4-(1,1-difluoro-ethyl)-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (430 mg, 1.46 mmol, 62%). ES-MS: m/z 296 [M+H]+, rt 6.05 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:4]=1[C:5](O)=[O:6])[CH3:2].S(Cl)([Cl:16])=O>>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:4]=1[C:5]([Cl:16])=[O:6])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cccc(CC)c1C(=O)O
Product: CCc1cccc(CC)c1C(=O)Cl

Procedure:
2,6-Diethylcyanobenzene was prepared by converting 2,6-diethylaniline to a diazonium salt and then reacting the diazonium salt with copper cyanide. Hydrolysis of 2,6-diethylcyanobenzene was effected by reaction with sodium hydroxide in ethylene glycol to provide 2,6-diethylaminocarbonyl benzene. The latter compound was reacted with phosphoric acid to provide 2,6-diethylbenzoic acid. Reaction of the benzoic acid with thionyl chloride afforded 2,6-diethylbenzoylchloride as an oil.