Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)(=[O:3])[CH3:2].[I:22](O)(=O)=O.II>C(O)C>[C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]=1[I:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)cc1NC(C)=O
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2ccccc2)c(I)c1NC(C)=O
Temperature: 50 °C
Yield: 325.2 %

Procedure:
A suspension of ethyl 2-(5-acetamido-3-phenyl-pyrazol-1-yl)acetate (37 g, 129 mmol), iodic acid (5.6 g, 32 mmol) and iodine (19.7 g, 77 mmol) in ethanol (400 mL) was heated at 50° C. for 2 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and the residue was eluted through a pad of silica gel with CH2Cl2 diethyl ether (1:0 to 97:3). The residue was partitioned between CH2Cl2 and 2 M Na2S2O3 aq. solution. The layers were separated and the organic washed was dried (MgSO4), and concentrated in vacuo to provide a residue that was partially purified by chromatography (silica gel, CH2Cl2/isohexane 1:1 to 1:0, then CH2Cl2/diethyl ether 9:1 to 8:2), then triturated with diethyl ether to provide the title compound as an off-white solid (43 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[C:23]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:22][CH:21]=[C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:23]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:22][CH:21]=[C:20]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 16.9 %

Procedure:
A suspension of 1F (650 mg, 1.29 mmol) and 5 wt % platinum on activated carbon (500 mg) in THF (60 mL) and MeOH (60 mL) was stirred at RT under H2 at 80 psi for 5 days. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a foam (110 mg, 17%). LC/MS (method A): retention time=3.82 min, (M+H)+=506.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4](=O)[O:3]1.[NH2:20][OH:21]>C(OCC)(=O)C>[OH:21][N:20]1[C:2](=[O:1])[C@@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4]1=[O:3]
Reactant: CC(C)C(=O)O[C@@H]1C(=O)OC(=O)[C@H]1OC(=O)C(C)C
Reactant: NO
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@@H]1C(=O)N(O)C(=O)[C@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of compound (2a) (5.98 g, 22 mmol) in ethyl acetate (50 mL) at 0° C. was added a 50% aqueous solution of hydroxylamine (1.75 g, 26.4 mmol). The resulting mixture was stirred at room temperature for 3 h and washed successively with aqueous citric acid solution and brine, then dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was suspended in toluene and the reaction mixture heated under reflux for 5 h, with the azeotropically liberated water being collected in a Dean-Stark apparatus. Toluene was removed in vacuo to afford the title compound (2b) (6.3 g, quantitative yield). 1H-NMR (400 MHz, CDCl3): δ 1.22 (d, J=6.8 Hz, 12H), 2.69 (hept, J=6.8 Hz, 2H), 5.48 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=O)[CH2:8]2.Cl.[NH2:17][OH:18]>C(O)C>[F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=[N:17][OH:18])[CH2:8]2
Reactant: NO
Reactant: O=C1CC2CCCC(C1)N2CC(F)(F)F
Agent: Cl
Solvent: CCO
Product: ON=C1CC2CCCC(C1)N2CC(F)(F)F

Procedure:
A mixture of 9-(2,2,2-trifluoro-ethyl)-9-aza-bicyclo[3.3.1]nonan-3-one (CAS no: 209054-63-7) (6.70 g, 30 mmol) in ethanol (100 mL) and hydroxylamine hydrochloride (2.23 g, 32 mmol) was refluxed for 6 h. The reaction mixture was evaporated totally, the residue extracted with dichloromethane and sodium carbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a light brown solid. (6.4 g, 89%); MS: m/e=237.1 (M+H+).
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][CH2:21][S:22][C:8]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1>[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2=[CH:8][S:22][CH:21]=[C:20]12
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: C[Si](C)(C)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.35 ml, 0.018 mol) is added to a cooled (ice bath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]-thieno[3,2-d]pyrimidine-7-carboxylic acid (4.5 g, 0.018 mol) in pyridine (35 ml) under nitrogen. The mixture is stirred at ice bath temperature for 1 hour and then allowed to warm at room temperature. N-chlorosuccinimide (2.44 g, 0.018 mol) is added and the mixture is heated at 95° C. for 20 minutes. The mixture is cooled, diluted with ice water (5 ml) and stirred for 15 minutes. The precipitate is filtered, washed with boiling acetone and dried to give the product (3.5 g.) mp 335° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[C:18]([F:26])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-hydroxypropionate (9.9 g, 25.5 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (25.5 ml, 51.0 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-hydroxypropionic acid (8.3 g, 90%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][CH:16]([NH:31][C:32](=[O:46])[CH:33]([N:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[CH3:34])[C:17](=[O:30])[CH2:18][O:19][C:20](=[O:29])[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28])=[O:14])(C)(C)C>ClCCl>[C:13]([CH2:15][CH:16]([NH:31][C:32](=[O:46])[CH:33]([N:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[CH3:34])[C:17](=[O:30])[CH2:18][O:19][C:20](=[O:29])[C:21]1[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=1[Cl:27])([OH:14])=[O:12]
Reactant: CC(C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c1c(Cl)cccc1Cl)n1ccc2ccccc2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)NC(CC(=O)O)C(=O)COC(=O)c1c(Cl)cccc1Cl)n1ccc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a stirred ice cold solution of 2,6-dichloro-benzoic acid 4-tert-butoxycarbonyl-2-oxo-3-[2-(1-oxo-1H-isoquinolin-2-yl)-propionylamino]-butyl ester (110 mg, 0.19 mmol) in anhydrous dichloromethane (2 ml). The mixture was stirred at 0° C. for 1 h and at room temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure and then the residue was redissolved in dry dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The residue was then lyophilized twice from HPLC grade water and then purified by reverse phase HPLC using a gradient eluent of 10:90 CH3CN:water to 100:0 CH3CN:water to afford the title compound as white solid (17 mg, 16%): IR (solid) 3295, 1736, 1648, 1618, 1590 cm−1; 1H NMR (400 MHz, DMSO) 1.57 (3H, 2×d), 2.64-2.80 (2H, m), 4.73 (1H, m), 5.14-5.33 (2H, m), 5.44-5.53 (1H, m), 6.67 (1H, m), 7.44-7.74 (7H, m), 8.20 (1H, d), 8.77-8.83 (1H, bd); 13C NMR (100 MHz, DMSO) 16.72, 16.90, 53.77, 105.36, 105.49, 125.48, 126.37, 126.90, 127.49, 128.85, 130.52, 130.67, 131.15, 132.47, 132.82, 132.93, 137.09, 137.12, 161.38, 163.56, 163.64, 171.15, 171.25; MS (FAB+ve, HR) Calculated for C24H20Cl2N2O7 (MH+) 519.0726, found 519.0701.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[CH3:25][N:26]([CH2:28][C@@H:29]1[CH2:31][C@H:30]1[C:32]1[C:40]2[C:35](=[CH:36][C:37]([C:41]#[N:42])=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[CH3:27].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:41]([C:37]1[CH:36]=[C:35]2[C:40]([C:32]([C@@H:30]3[CH2:31][C@H:29]3[CH2:28][N:26]([CH3:27])[CH3:25])=[CH:33][N:34]2[C:2]2[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:39][CH:38]=1)#[N:42]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Reactant: CN(C)C[C@@H]1C[C@H]1c1c[nH]c2cc(C#N)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Product: CCN(Cc1ccc(OC)cc1)c1nc(-n2cc([C@@H]3C[C@H]3CN(C)C)c3ccc(C#N)cc32)nn2c(C#N)cnc12
Temperature: 110 °C
Yield: 78 %

Procedure:
A 5 ml microwave vial was loaded with 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 10) (110 mg, 0.321 mmol), rac-3-((1r,2r)-2-((dimethylamino)methyl)cyclopropyl)-1H-indole-6-carbonitrile (50 mg, 0.209 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Brettphos (CAS 1070663-78-3) (35 mg, 0.065 mmol) and Cs2CO3 (powder, 80 mesh, 210 mg, 0.645 mmol). The vial was sealed, evacuated and flushed with nitrogen 4×. Dioxane (3 ml) was added and the vial evacuated and backfilled with nitrogen 4 times. The reaction was heated to 110° C. for 12 hours. LCMS shows m/e+=546, consistent with [M+H]+ of product. Only trace of indole starting material remaining. The reaction mixture was allowed to cool to room temperature, diluted with acetonitrile and filtered through Celite. The Celite was washed with acetonitrile. The combined solutions were evaporated to dryness. The crude was purified by column chromatography on silica. (40 g cartridge, load sample as solution in dichloromethane, elute with gradient from 100% DCM to 100% EtOAc (product doesn't elute), then a gradient from 100% dichloromethane to 80% DCM+20% (MeOH+1% aq, conc. NH4OH). Product containing fractions were combined and evaporated to dryness to give 92.8 mg pale yellow film (+/−)-2-(6-cyano-3-((1r,2r)-2-((dimethylamino)methyl)cyclopropyl)-1H-indol-1-yl)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (92.8 mg, 0.163 mmol)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.Cl.[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][CH:16]2[CH2:17][CH2:18][C:13]([F:20])([F:12])[CH2:14][CH2:15]2)[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)nc(NC2CCC(F)(F)CC2)c1C
Temperature: 50 °C
Yield: 68.2 %

Procedure:
To the solution of 2,4-dichloro-5,6-dimethylpyrimidine (0.585 g, 3.304 mmol, Example 1, Step C) in N,N-dimethylformamide (10 mL), (4,4-difluorocyclohexyl)amine hydrochloride (0.652 g, 3.800 mmol) and triethylamine (1.338 g, 13.218 mmol) were added, and reaction mixture was heated at 50° C. overnight. Volatiles were removed under reduced pressure, and the residue was poured into water (300 mL). The mixture was extracted with ether (3×50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was subjected to column chromatography on silica eluting with a mixture of hexane/ethyl acetate (gradient 4:1-2:1) to provide 621 mg (68%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.18-1.24 (m, 1H), 1.60-1.72 (m, 2H), 1.80-2.10 (m, 8H) 2.21 (s, 3H), 4.00-4.10 (m, 1H), 6.73 (d, J=7.79 Hz, 1H); MS (ESI) m/z 318.6 (M+1)+.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 2-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1M Na((TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=1)(C)(C)C.[ClH:19]>ClCCl>[ClH:19].[CH:15]([C:12]1[N:11]=[C:10]([CH2:9][CH2:8][NH2:7])[O:14][N:13]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1noc(CCNC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1noc(CCN)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
900 mg (3.53 mmol) tert-butyl[2-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamate are placed in 10 ml dichloromethane, 20 ml 1 molar ethereal hydrochloric acid are added. The reaction mixture is stirred for 16 hours at ambient temperature. After the addition of a further 10 ml ethereal hydrochloric acid the mixture is stirred for another 72 hours at ambient temperature and 4 hours at 40° C. The suspension is evaporated down. The residue is dissolved in acetone, mixed with diethyl ether and suction filtered.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH:12][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC#CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of (4-Amino-but-2-ynyl)-carbamic acid tert-butyl ester (0.8 g, 4.34 mmol) in dry CH2Cl2 (40 ml) was added 6,6-bis-(4-fluorophenyl)-hexanoic acid (1.32 g, 4.4 mmol) under nitrogen. To the reaction was added EDC (1.66 g, 8.68 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give the desired product in 72% yield.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:35])[C:4](=[O:34])[CH2:5][C:6](=[O:33])[C@@H:7]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10].O.CS([N:41]=[N+:42]=[N-])(=O)=O.N12CCCN=C1CCCCC2>C(#N)C.C(OCC)C>[N+:41](=[C:5]([C:4]([N:3]([O:2][CH3:1])[CH3:35])=[O:34])[C:6](=[O:33])[C@@H:7]([NH:13][C:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N-:42]
Reactant: CS(=O)(=O)N=[N+]=[N-]
Reactant: COC(=O)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)CC(=O)N(C)OC
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)C(=[N+]=[N-])C(=O)N(C)OC
Reaction time: 4 h
Yield: 94 %

Procedure:
β-ketoamide 13 (3.70 g, 7.80 mmol, 1.0 equiv) was dissolved in 20.0 mL of acetonitrile (0.37 M) and H2O (0.14 mL, 1.0 equiv). Diazo transfer reagent, MeSO2N3 (1.02 mL, 11.70mmol, 1.5 equiv) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.75 mL, 11.70 mmol, 1.5 equiv) were sequentially added. The resulting reaction mixture was permitted to stir for 4 h and then this reaction mixture was diluted with diethyl ether. The organic phase was washed sequentially with 10% NaOH, water, and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo. The oil was diluted in 1/1 ethyl acetate/hexanes and loaded onto a small plug of silica. The plug was eluted with 1/1 ethyl acetate/hexanes and the organics concentrated to provide the pure product 14 as a pale yellow foam (3.67 g) representing a 94% yield. X-ray quality crystals were grown from EtOAc/hexanes. m.p.=130-131° C.; [α]D27=−68.4° (c=4.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.47-7.49 (m, 6H); 7.19-7.22 (m, 6H), 7.13 (tt, J=1.6, 7.3 Hz, 3H), 4.88 (dt, J=5.7, 11.1 Hz, 1H), 3.68 (s, 3H); 3.60 (s, 3H); 3.11 (s, 3H), 2.74 (dd, J=6.1, 13.8 Hz, 1H); 2.61 (dd, J=6.1, 13.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 193.74, 161.01, 145.24, 128.04, 126.72, 125.31, 70.06, 60.18, 55.19, 50.77, 39.07, 32.65; IR (thin film): 3057, 2948, 2118, 1736, 1638, 1596, 1490, 1461, 1447, 1373, 1267, 1192, 1162, 1113, 1028, 940, 904, 776, 736, 706, 644 cm−1; HRMS [M+Na] for C28H28N4O5Na, calcd., 523.19519, found, 523.19997 (Error=9.1333 ppm).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1.Br[C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][C:23]=1[CH3:29]>>[CH3:29][C:23]1[CH:24]=[C:25]([C:27]#[N:28])[S:26][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1
Reactant: CC1(c2ccccc2)OCC(=O)Nc2ccc(Br)cc21
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2

Procedure:
Prepared from 7-bromo-5-methyl-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-4-methyl-thiophene-2-carbonitrile using the coupling procedures of examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.15 (s, 1H), 7.85 (s, 1H), 7.49 (m, 1H), 7.38-7.21 (m, 7H), 4.29 (d, J=15.19 Hz, 1H), 4.04 (d, J=15.05 Hz, 1H), 2.22, (s, 3H), 1.93 (s, 3H); MS (ES) m/z 375 ([M+H]+, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][C:30]1([CH3:37])[O:34][CH:33]([CH2:35][NH2:36])[CH2:32][O:31]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>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].C(Cl)Cl.O1CCOCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:36][CH2:35][CH:33]5[CH2:32][O:31][C:30]([CH3:37])([CH3:29])[O:34]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC1(C)OCC(CN)O1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)OCC(CNc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)O1
Temperature: 112 °C
Yield: 67.3 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), C-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-methyl-amine (101 mg, 0.86 mmol), Pd2(dba)3 (66 mg, 0.072 mmol), Xphos (34 mg, 0.072 mmol), t-BuONa (138 mg, 1.44 mmol) and dioxane (2 mL) was added in a 10 mL of sealed tube. The reaction mixture was heated by microwave at 112° C. for 7 min under N2. The reaction mixture was filtered to gather the solution. Then water was added in the solution and extracted by DCM (3×50 mL); The combined organic layer was dried by Na2SO4, concentrated in vacuo, separated by TLC (DCM) to {2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-amine (248 mg, yield: 67%). 1H NMR (DMSO-d6, 400 MHz): δ8.16 (s, 1H), 7.79 (q, J=2.8, 8.4 Hz, 1H), 7.76-7.55 (m, 1H, 7.31 (t, J=8.4 Hz, 1H), 6.99 (t, J=4.4 Hz, 1H), 6.52 (t, J=6.0 Hz, 1H, 6.33 (d, J=8.4 Hz, 1H), 4.12-3.81 (m, 5H), 3.52-3.49 (m, 2H), 2.96 (t, J=4.8 Hz, 2H), 1.87 (s, 2H), 1.18 (d, 6H) LC-MS (ESI): m/z=512 [M+H]+
Reaction SMILES: OC#CC1C=CC=CC=1.[CH3:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.N.[Na].[Cl-].[NH4+]>O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]#[CH:10])=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Agent: OC#Cc1ccccc1
Solvent: O
Product: C#Cc1ccc(O)cc1
Yield: 46 %

Procedure:
The conventional preparation process of hydroxyphenyl-acetylene has been reported, for example, in Izv. Akad. Nauk SSSR Se. r. Khim 1964(11), 2073-4. In the process, 4-hydroxyacetophenone is chlorinated with phosphorus pentachloride, reacted in liquid ammonia in the presence of metallic sodium and ammonium chloride, and successively treated with water to obtain 4-hydroxyphenylacetylene in 46% yield.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>O1CCCC1>[C:11]1([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[N:3][NH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: c1ccc2cnncc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=NNC(c2ccccc2)c2ccccc21

Procedure:
A solution of 4 g of phthalazine in 50 ml of tetrahydrofuran is added dropwise at room temperature to a solution of phenyl-magnesium bromide (prepared from 6 g of bromobenzene and 1 g of magnesium in 30 ml of tetrahydrofuran). The reaction mixture is held at reflux for 6 hrs. After cooling the mixture is treated with a saturated aqueous solution of ammonium chloride and extracted 3 times with diethyl ether. The organic phases are combined, dried and subsequently triturated with pentane. 2.32 g of not quite pure 1-phenyl-1,2-dihydro-phthalazine are isolated as a yellowish solid, m.p. 79° C.