Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=2)=[CH:3]1.P(Cl)(Cl)([Cl:23])=O>CN(C=O)C>[Cl:23][C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C)c1ccc(-c2cn[nH]c(=O)c2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(-c2cnnc(Cl)c2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-[4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl]propanoate (0.48 g, 1.7 mmol) in phosphoryl chloride (5.0 mL) and DMF (50 μL) was stirred at 100° C. for 3 h. The solvent was removed and the residue was diluted with methylene chloride, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in methylene chloride (0-20%) to afford the desired product. LCMS (M+H)+: m/z=299.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.[BH3-]C#N.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:20]2[CH2:22][CH2:21]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of 14.0 g (0.0699 mol) piperidin-4-yl-carbamic acid tert-butyl ester in 500 mL abs. MeOH 250 g of dried molecular sieves 3 Å were added. Under argon 39.9 mL (0.699 mol) acetic acid and 52.5 mL (0.262 mol) (1-ethoxy-cyclopropoxy)-trimethyl-silane were added. Finally 314.5 mL (0.3145 mol) of a 1 M NaCNBH3-solution in THF were added dropwise. After 20 min at room temperature the reaction mixture was stirred for 6 h at 60° C. The mixture was filtered over “Celite”. The filtrate was concentrated under reduced pressure. The resulting residue was taken up in 700 mL ethyl acetate and washed with 250 mL of a 1 M NaOH-solution. The aqueous layer was extracted with 300 mL ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under vacuo to give crude (1-cyclopropyl-piperidin-4-yl)-carbamic acid tert-butyl ester as a colorless solid.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10][CH:11]([CH3:12])[C:5]2=[N:4][N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:12][CH:11]1[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[N:6]2[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:3][N:4]=[C:5]12
Reactant: C1CNCCN1
Reactant: CC1N=C(c2ccccn2)c2ccccc2-n2c(Br)nnc21
Product: CC1N=C(c2ccccn2)c2ccccc2-n2c1nnc2N1CCNCC1

Procedure:
In the manner given in Example 1, 1-bromo-4-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with piperazine to give 4-methyl-1-(piperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=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.[NH2:58][CH2:59][C:60]12[CH2:69][CH:64]3[CH2:65][CH:66]([CH2:68][C:62]([C:70]([O:72][CH3:73])=[O:71])([CH2:63]3)[CH2:61]1)[CH2:67]2>CN(C=O)C.C(#N)C.O>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([NH:58][CH2:59][C:60]34[CH2:69][CH:64]5[CH2:65][CH:66]([CH2:68][C:62]([C:70]([O:72][CH3:73])=[O:71])([CH2:63]5)[CH2:61]3)[CH2:67]4)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1
Reactant: COC(=O)C12CC3CC(CC(CN)(C3)C1)C2
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(CNC(=O)c4c(C)nn5c(OCc6c(F)cccc6F)cc(C)cc45)(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
A mixture of 52 mg of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (75% purity, 0.118 mmol) from Example 4A, 72 mg of HATU (0.188 mmol) and 0.138 ml (0.792 mmol) of N,N-diisopropylethylamine in 0.7 ml of DMF was stirred at RT for 10 min. Subsequently, 53 mg (0.236 mmol) of methyl 3-(aminomethyl)adamantane-1-carboxylate from Example 37A in 0.5 ml of DMF were added and the mixture was stirred at RT overnight. The reaction mixture was admixed with water and acetonitrile and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.05% formic acid). 35 mg of the target compound were obtained (53% of theory).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>C(N(CC)CC)C>[F:17][C:18]([F:31])([F:32])[O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:22][CH:21]=1
Reactant: NCCCOc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCOc1ccc(OC(F)(F)F)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.88 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 3-(4-trifluoromethoxyphenoxy)propylamine (1.18 g) and triethylamine (0.50 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13].[F:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]2[N:29]=[C:28]([CH2:30]O)[CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH2:30][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([O:23][C:22]2[CH:32]=[CH:33][C:19]([F:18])=[CH:20][CH:21]=2)[N:29]=1)=[O:13]
Reactant: OCc1cccc(Oc2ccc(F)cc2)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccc(F)cc2)n1)c1ccc2ccccc2c1

Procedure:
The acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid is reacted with [6-(4-fluorophenoxy)-2-pyridyl]methanol using the procedure of Example 1 to give [6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-naphthyl)-3methylbutanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](I)=[CH:7][C:6]([C:10](=[O:26])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][C:4]=1I.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[CH:28]([C:30]1[CH:31]=[C:32]([C:4]2[CH:5]=[C:6]([C:10](=[O:26])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:7]=[C:8]([C:4]3[CH:3]=[CH:8][CH:7]=[C:6]([CH:10]=[O:26])[CH:5]=3)[C:3]=2[O:2][CH3:1])[CH:33]=[CH:34][CH:35]=1)=[O:29]
Reactant: COc1c(I)cc(C(=O)NCCCCCCCCc2ccccc2)cc1I
Reactant: O=Cc1cccc(B(O)O)c1
Product: COc1c(-c2cccc(C=O)c2)cc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1cccc(C=O)c1

Procedure:
The title compound was prepared as a solid (0.479 g, 75%) from 2,6-diiodo-4-(8-phenyl-octylcarbamoyl)phenyl methyl ether using 3-formylbenzeneboronic acid and a procedure similar to step 3 of Example 93; 1H NMR (DMSO-d6) δ 1.21-1.35 (m, 8H), 1.46-1.60 (m, 4H), 2.47-2.58 (m, 2H), 3.13 (s, 3H), 3.21-3.32 (m, 2H), 7.09-7.19 (m, 3H), 7.21-7.30 (m, 2H), 7.54 (t, J=7.5 Hz, 2H), 7.94-8.03 (m, 6H), 8.17 (s, 2H), 8.61 (t, J=5.6 Hz, 1H), 10.14 (s, 2H); mass spectrum [(+) ESI], m/z 548 (M+H)+, 570 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:27]([CH3:29])[CH3:28])[CH2:11][C@H:12]1[C:17]([O:18][CH2:19][CH3:20])=N[C@H](C(C)C)C(OCC)=[N:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=[O:32].[Na+]>CC#N>[NH2:13][C@@H:12]([CH2:11][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:27]([CH3:29])[CH3:28])[C:17]([O:18][CH2:19][CH3:20])=[O:32]
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1C[C@H](COCc1ccccc1)C(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)[C@@H](N)C[C@H](COCc1ccccc1)C(C)C
Reaction time: 1.5 h

Procedure:
To a solution of (2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (17.5 g, 46.8 mmol) in CH3CN (187 mL) was added 1 N aq HCl (187 mL, 187.2 mol) at rt and stirring was continued for 1.5 h. The mixture was poured into ice-cold, satd aq NaHCO3 and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried and evaporated to afford (2S,4S)-ethyl 2-amino-4-(benzyloxymethyl)-5-methylhexanoate as a pale yellow oil (13.5 g) which was used in the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[C:10](OCC)=[O:11])=[CH:5][CH:4]=1)#[N:2].[CH3:16][C@H:17]1[CH2:22][C@@H:21]([OH:23])[C@H:20]([CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1>CC(OC)(C)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:15])[C:10]([O:23][C@@H:21]2[CH2:22][C@H:17]([CH3:16])[CH2:18][CH2:19][C@H:20]2[CH:24]([CH3:26])[CH3:25])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CCOC(=O)C(=O)c1ccc(C#N)cc1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: COC(C)(C)C
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)c1ccc(C#N)cc1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
A mixture of ethyl (4-cyanophenyl)(oxo)acetate (35.2 g, 173 mmol), (1R,2S,5R)-(−)-menthol (41.0 g, 262 mmol), and titanium ethoxide (3.6 mL, 17 mmol) was heated to 80 ° C. under vacuum for 60 hours. The mixture was diluted with MTBE (1.5 L), washed sequentially with 10% HCl (2×300 mL), saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide the desired product (50.0 g, 92% yield). 1H NMR (CDCl3) δ 8.12 (m, 2H), 7.82 (m, 2H), 5.01 (ddd, 2H), 2.15 (m, 1H), 1.91 (m, 1H), 1.72 (m, 2H), 1.55 (m, 2H), 1.16 (m, 2H), 0.97(d, 3H), 0.91 (d, 3H), 0.83 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([CH2:25][OH:26])=[CH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:16]([CH:25]=[O:26])=[CH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A mixture of [1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]methanol (19.00 g), activated manganese dioxide (41.19 g), and tetrahydrofuran (300 ml) was stirred at room temperature overnight. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carbaldehyde (18.56 g, yield: 98%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 100–101° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[N:15]([CH3:26])[N:16]=[N:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][C:41]([C:44]3([C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])=[O:48])[CH2:46][CH2:45]3)=[CH:40][CH:39]=2)O1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].Cl[Pd]Cl>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[N:15]([CH3:26])[N:16]=[N:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([C:38]3[CH:39]=[CH:40][C:41]([C:44]4([C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])=[O:48])[CH2:46][CH2:45]4)=[CH:42][CH:43]=3)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](OC(=O)Nc1c(-c2ccc(Br)cc2)nnn1C)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)nnn1C)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 41.8 %

Procedure:
In a 20 mL vial, [5-(4-bromo-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester (123.7 mg, 264 μmol), N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide (110 mg, 301 μmol), DPPF (36 mg, 64.9 μmol) and PdCl2(dppOCH2Cl2 (40 mg, 49.0 μmol) were combined with DMF (5 mL, with nitrogen bubbled through for 20 min) to give a light brown/red solution. To this was added 2N Na2CO3 (527 μl, 1.05 mmol, with nitrogen bubbled through for 20 min), the red mixture (looked like salt precipitated) had nitrogen bubbled through for 1 min. The vial was sealed, placed in a dry block, and heated at 80° C. for 4 hr. The reaction was diluted with ethyl acetate (75 mL) and 0.1 M HCl (100 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (75 mL). The organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and dried from DCM/hexanes to give a crude material (311 mg). The crude material was dissolved in minimal DCM and purified by flash chromatography (silica gel, 24 g Redisep, 30 mL/min, 0% to 100% EtOAc in hexanes, 0.5% AcOH). Appropriate fractions were combined, concentrated, dried from DCM/hexanes to yield {5-[4′-(1-methane-sulfonylamino carbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-3H-[1,2,3]triazol-4-yl}-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester (69.2 mg, 41.8% yield) as a brown solid. C30H28F3N5O5S (m/e) 627, obsd. 628 (M+H, ES+). 1H NMR (DMSO-d6) δ ppm 11.16 (br. s., 1H), 9.47-10.15 (m, 1H), 7.53-7.94 (m, 10H), 7.41 (d, J=8.3 Hz, 2H), 5.89 (br. s., 1H), 3.86 (br. s., 3H), 3.20 (s, 3H), 1.60 (br. s., 3H), 1.47-1.53 (m, 2H), 1.20 (d, J=1.8 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:29])CC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: ClCCl
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 20 h
Yield: 39.8 %

Procedure:
(1,4-Dibenzylpiperazin-2-yl)methanol (15 g, 50.5 mmol) in DCM (50 mL) was added dropwise to a stirred solution of DAST (7.42 mL, 60.6 mmol) in DCM (150 mL) cooled to −78° C. The reaction mixture was maintained below −30° C. for 24 h before warming to room temperature and stirring for an additional 20 h. The reaction was quenched by the addition of water (100 mL). The organic phase was separated, the aqueous basified with NaOH (aq.) to pH 10 and extracted with DCM (3×75 mL). The combined organics were washed with water (2×100 mL), brine (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The resultant oil was purified by chromatography on silica gel with EtOAc:heptane (1:9, v/v) as eluent to afford 1,4-dibenzyl-2-fluoromethylpiperazine (6.0 g, 20.1 mmol, 40%). A biproduct of the reaction was also isolated, 1,4-dibenzyl-6-fluoroperhydro-1,4-diazepine (1.0 g, 3.35 mmol, 7%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH2:7][N:8]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1)(=O)[CH3:2]>C1(C)C(C)=CC=CC=1>[Cl:16][C:14]1[S:13][C:11]2[N:12]3[C:1]([CH3:2])=[N:4][N:5]=[C:6]3[CH2:7][N:8]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:10]=2[CH:15]=1
Reactant: CC(=O)NNC1=Nc2sc(Cl)cc2C(c2ccccc2F)=NC1
Solvent: Cc1ccccc1C
Product: Cc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
6.8 g of 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine are refluxed for 9 hours in 300 ml of absolute xylene. After cooling, the precipitated impurities are filtered off under vacuum. The solvent is then evaporated under reduced pressure and the product recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-fluorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 187°-189° C.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]>[Pd].CO>[F:26][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH2:22]3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: CN1c2nc(C3=CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: [Pd]
Solvent: CO
Product: CN1c2nc(C3CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reaction time: 0.5 h

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclo-penta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (24-2, 100 mg, 0.26 mmol, 1.0 equiv) was added to anhydrous methanol (2.6 mL). To this solution was added 10% palladium(0) on carbon (55.7 mg, 0.052 mmol, 0.2 equiv) to give a black suspension. The reaction flask was evacuated and back-filled with hydrogen from a balloon. This process was repeated an additional 2 times. The resulting mixture was allowed to stir under an atmosphere of H2 for 30 min. Following this duration, LCMS showed complete consumption of starting material. The reaction contents were filtered through Celite, washed with DCM and concentrated to give 25-1 as an off-white solid. The crude material was carried forward without additional purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[C:12]=2[Cl:15])[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO>[CH:27]1([O:26][C:20]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([NH:17][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[C:12]=3[Cl:15])[CH2:7]2)=[O:31])[CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(Cl)c(Cl)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(Cl)c(Cl)c3C2)c1OC1CCC1
Temperature: 25 °C

Procedure:
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-4,5-dichloro-indan-2-carboxylic acid ethyl ester (255) (460 mg, 0.99 mmol) is dissolved in EtOH (50 mL) and set to stir at RT. To this solution is added 5M KOH (3 ml). The reaction mixture is stirred at RT overnight. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with concentrated HCl to pH 2. The resultant mixture is washed with EtOAc (3×100 ml). Organics are combined and washed with brine, then dried over anhydrous Na2SO4 and concentrated in vacuo. The desired product (256) is obtained as white solid (405 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>O1CCCC1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1cc(N)cc(OC)c1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Yield: 97.4 %

Procedure:
To 3,5-dimethoxyaniline (20 g, 131 mmol) dissolved in anhydrous tetrahydrofuran (90 mL) was added 4-(dimethylamin) pyridine (1.6 g, 13.1 mmol) and ethyl trifluoroacetate (47 mL, 392 mmol). After refluxing 48 hours, the cooled reaction mixture was concentrated and partitioned between ethyl acetate (300 mL) and 2N hydrochloric acid (100 mL). The ethyl acetate layer is washed with water (100 mL), dried using anhydrous sodium sulfate, and concentrated to yield N-(3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (31.8 g, 98%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]N(C)C=O>[Cl-].[Na+].O>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([CH3:32])[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Nc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1c2ccccc2CN(C(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21

Procedure:
[1,1′-Biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone of Example 6 (0.97 g) was added to sodium hydride (2 equivalents, 60% in oil, washed with hexane) and N,N-dimethylformamide (25 mL). lodomethane (0.45 g) was added and after overnight stirring, the mixture was poured into brine. The precipitate was collected, redissolved in dichloromethane and the solution filtered through a short column of Magnesol®. The column was rinsed with several volumes of dichloromethane, and the combined eluate refluxed with the gradual addition of hexane until incipient crystallization. Cooling and filtration provided the title compound (0.89 g), m.p. 198–201° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[O:11]=[C:12]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])(C)C)=[O:20])[CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Ca+2].[Cl-]>ClC1C=CC=CC=1Cl.C(O)C.[Cu].[Zn]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[C:12](=[O:11])[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:25]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[O:20])[CH2:15][CH2:14]2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CCC2=O)cc1

Procedure:
4-Iodonitrobenzene and tert-butyl 5-oxo-[1,4]diazepan-1-carboxylate were allowed to undergo the reaction in 1,2-dichlorobenzene in the presence of copper powder and potassium carbonate, and then the nitro group was reduced in ethanol using zinc powder and calcium chloride to obtain benzyl 4-(4-aminophenyl)-5-oxo-1,4-diazepan-1-carboxylate. ESI: 340.