Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:12][O:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5](/[CH:4]=[CH:3]/[CH2:2][OH:1])[CH:6]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: OC/C=C/c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2cccc(/C=C/CO)c2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of (E)-3-(3-Hydroxy-propenyl)-phenol (0.5 g, 3.33 mmol), methyl 4-(bromomethyl) benzoate (763 mg, 3.33 mmol) and potassium carbonate (1.8 g, 13.3 mmol) in acetone (40 ml) was stirred at room temperature over night. The reaction mixtyre was added water (30 ml) and acidified with 1N HCl and extracted with ethyl acetate (90 ml). The organic phase was washed with water, brine and dried with sodium sulphate and evaporated and dried in vacuo yielding 954 mg (96%) (E)-4-[3-(3-Hydroxy-propenyl)-phenoxymethyl]-benzoic acid methyl ester.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si]([O:24][C:25]1[CH:30]=[C:29]([O:31][Si](C(C)(C)C)(C)C)[CH:28]=[CH:27][C:26]=1[C@@H:39]1[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]1)(C(C)(C)C)(C)C>CN(C)C1C=CN=CC=1.ClC(Cl)C>[OH:24][C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:26]=1[C@@H:39]1[CH2:40][CH2:41][C@H:42]([NH:45][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:43][CH2:44]1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=C(Nc1ccccc1)N[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Reaction time: 60 h
Yield: 40.4 %

Procedure:
A solution of phenylisocyanate (0.015 ml, 0.13 mmol), triethylamine (0.03 ml), 4-dimethylaminopyridine (catalytic) and cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexylamine (0.043 g) in dichloroethane (4 ml) was stirred at room temperature for 17 hr. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate (5 ml) and dichloromethane (5 ml). The aqueous phase was extracted with dichloromethane (2×5 ml) and the combined organic extracts washed with brine (7 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in dichloromethane (6 ml) and stirred rapidly with water (3 ml) and trifluoroacetic acid (3 ml) for 60 hr. Toluene (15 ml) was added and the solution concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether) afforded the title compound (0.013 g, 30%) as a colourless solid. 6H (CD3OD) 1.32-1.46 (2H, m), 1.53-1.69 (2H, m), 1.90 (2H, m), 2.17 (2H, m), 2.83 (1H, m), 3.65 (1H, m), 6.28 (2H, m), 6.94 (1H, d), 7.00 (1H, m), 7.27 (2H, m) and 7.38 (2H, m); m/s(ES+) 327.20 (M+H)+.
Reaction SMILES: C(O)(C)C.[CH3:5][C:6]1([CH3:14])[CH:12]2[CH2:13][CH:7]1[CH2:8][CH2:9][C:10]2=[CH2:11].[S:15](=[O:18])([OH:17])[O-:16].[NH4+:19]>O>[C:10]1([CH2:11][S:15]([O-:18])(=[O:17])=[O:16])[CH2:12][CH2:13][C@H:7]([CH:6]([CH3:14])[CH3:5])[CH2:8][CH:9]=1.[NH4+:19]
Reactant: O=S([O-])O
Reactant: C=C1CCC2CC1C2(C)C
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)[C@@H]1CC=C(CS(=O)(=O)[O-])CC1
Reaction time: 22 h

Procedure:
Into a 1 liter flask equipped with magnetic stirrer were placed 450 ml isopropanol, 240 ml water and 54.4 grams (0.4 mole) β-pinene. Ammonium bisulfite, 105 grams (45%) was then added thereto. The mixture was stirred at 40°-45° C. for 22 hours. Thereafter, the solution was evaporated to dryness. Residue was extracted with methanol. The methanolic solution was filtered, and the resultant filtrate evaporated to dryness. Obtained were 84 grams product (85.8% purity; 77% yield).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN1C(=O)CCC1.O>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
5-Fluoro-2-nitrophenylamine (1.0 eq) and morpholine (3.0 eq) were dissolved in NMP and heated at 100° C. for 1 hour. The solution was cooled to room temperature and diluted with water. The resulting precipitate was filtered and dried under vacuum to yield 5-morpholin-4-yl-2-nitrophenylamine. The resulting solid was recrystallized from EtOH to afford pure product as a bright yellow solid. LC/MS m/z 224.1 (MH+), Rt 1.89 minutes.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14](=O)[NH:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1.CN.[CH:29]([N:32](C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN([PH+](N(C)C)N(C)C)C>CN(C=O)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:32][CH3:29])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Agent: CN
Agent: CN(C)[PH+](N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nnc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (585 mg, 1.216 mmol), methylamine (1.82 mL of 2 M in THF, 3.65 mmol) and diisopropylethylamine (0.42 mL, 2.43 mmol) in DMF (1.5 mL) was added 1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (V) (591 mg, 1.33 mmol). The reaction was stirred at RT for 18 h, then diluted with H2O (5 mL) and extracted with EtOAc (2×15 mL). The combined organic solution was washed with brine, dried over MgSO4, and concentrated. The residue was suspended in 5 mL of EtOAc, and filtered to 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine (507 mg, 84%) as an off white crystalline solid. MS (ESI, pos. ion) m/z: 495.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (1H, s), 8.13 (1H, d, J=8.8 Hz), 7.98 (2H, d, J=8.4 Hz), 7.91 (1H, m), 7.71 (1H, m), 7.70 (1H, m), 7.44 (2H, d, J=8.0 Hz), 2.88 (3H, d, J=4.9 Hz), 2.35 (3H, s).
Reaction SMILES: C(O)(=O)C.[C:5]([C:7]1[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=1)#[CH:6].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1)#[CH:6]
Reactant: C1CCNC1
Reactant: C#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C#Cc1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Glacial acetic acid (0.2 mL) was added to a mixture of 4-ethynylbenzaldehyde (1 g, 7.5 mmol), pyrrolidine (1.2 mL, 15 mmol) and NaBH(OAc)3 (2.5 g, 11.5 mmol) in DCE (35 mL). The resulting mixture was stirred for 2 h at rt. The reaction was quenched with saturated aqueous NaHCO3 (50 mL). The product was extracted into CH2Cl2 (2×100 mL), and the combined organic layer was washed with brine (25 mL), dried (MgSO4) and evaporated in vacuo to give 1-(4-ethynylphenyl)pyrrolidine in quantitative yield. 1H NMR (CDCl3) δ: 7.45 (d, J=7.8 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 3.62 (s, 2H), 3.06 (s, 1H), 2.51 (bs, 4H), 1.80 (bs, 4H).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC(=O)C=Cc1cc(Cl)ccc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C1CC(=O)CC(c2cc(Cl)ccc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (7.4 g) was added at room temperature diethyl malonate (3.6 g), and then added little by little 4-(5-chloro-2-fluorophenyl)-3-buten-2-one (4.3 g). The mixture was stirred at room temperature for 30 minutes and then for 2 hours while heating, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (17 ml), and the mixture was refluxed for 1 hour and cooled. To the mixture was added 2.5M sulfuric acid (17 ml) for 10 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-chloro-2-fluorophenyl)cyclohexane-1,3-dione (4.1 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[C:20]12([N:30]=[C:31]=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][C:31]([NH:30][C:20]12[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2)=[O:32])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)NC12CC3CC(CC(C3)C1)C2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a mixture of (S)-methyl 2-amino-3,3-dimethylbutanoate (200 mg, 1.377 mmol) and DIEA (0.481 mL, 2.75 mmol) in DCM (2 mL) solution was added 1-adamantyl isocyanate (334 mg, 1.515 mmol). The reaction mixture was stirred at rt overnight. The compound was purified by silica gel column chromatography (20% EtOAc/80% hexane) to give a white solid (265 mg, 59%) as product.
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]>O.Cl>[NH2:3][C:2]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[N:1][C:4]#[N:5]
Reactant: N#C[N-]C#N
Reactant: COC(=O)c1cccc(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc(NC(N)=NC#N)c1

Procedure:
To sodium dicyanamide in 5 mL of deionized water was added dropwise a solution of methyl 3-aminobenzoate (Aldrich, 1.30 g, 8.6 mmol) in 15 mL of 1N HCl. The resulting clear solution was heated at 80°-90° C. for 2 h. The precipitate was collected through filtration, crystallized from chloroform-methanol, dried in air followed by drying in a pistol at acetone reflux in vacuo to give 1.84 g (quantitative) of methyl 3-[amino(cyanoiminomethyl)]aminobenzoate as a white solid, mp 203°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:21])[F:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
130 mg (purity 93%, 0.35 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/methanol gradient). Yield: 104 mg (56% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:25]=[C:26]([NH:30][C:10]([NH:9][C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])=[O:11])[CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=C=Nc1c(F)cccc1F
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Solvent: c1ccncc1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3c(F)cccc3F)c1)cn2C1CCCC1
Temperature: 90 °C
Yield: 18.9 %

Procedure:
2,6-Difluorophenyl isocyanate (36.1 mg, 0.233 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (50 mg, 0.15 mol) in pyridine (3 mL). The resulting solution was heated to 90° C. for 3 h. The reaction was quenched with water and concentrated. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) afforded the title compound as a yellow solid (21 mg, 28%). MS: 477.2/322.2 (MH+); HPLC Rf: 5.66 min. (HPLC method
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[C-]#N.[Na+].[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:17]
Reactant: CCO
Reactant: Clc1ccc2nc(Cl)nnc2c1
Agent: [C-]#N
Agent: [Na+]
Product: CCOc1nnc2cc(Cl)ccc2n1

Procedure:
A suspension of 20.2 g (0.1 mole) of 3,7-dichlorobenzo-1,2,4-triazine and 12.2 g (0.25 mole) of sodium cyanide in 200 ml of ethanol was boiled under reflux for 2 hours. The salts were filtered off and the filtrate was evaporated in vacuo. The residue was stirred with water and cooled in ice for some time. The crystallized mass was filtered off and recrystallized from wash benzine. 17.6 g, that is to say 84% of theory, of 3-ethoxy-7-chloro-benzo-1,2,4-triazine with a melting point of 90°-92° C were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([CH2:23][F:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([CH2:23][F:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(CF)c(F)c2=O)c(F)cc1Cl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c(F)c(CF)n(C)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-fluoro-4-fluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-fluoro-4-fluoromethyl-3methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 85°-89° C.,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([CH:11]1[CH2:13][CH2:12]1)[NH2:10].CCN(C(C)C)C(C)C.CN([CH:26]=[O:27])C>CCOC(C)=O.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.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:26](=[O:27])[NH:10][CH:9]2[CH:11]1[CH2:13][CH2:12]1
Reactant: NC(c1cc(Cl)ccc1Br)C1CC1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1NC(C2CC2)c2cc(Cl)ccc21
Temperature: 130 °C
Yield: 68.7 %

Procedure:
A mixture of (2-bromo-5-chlorophenyl)(cyclopropyl)methanamine (2 g, 7.7 mmol), Pd(dppf)Cl2 (0.2 g), DIPEA (3 g, 23.1 mmol) in 20 mL of DMF was heated in an autoclave at 130° C. under 2 MPa of CO (g) for 16 hours. After the reaction, the mixture was diluted with AcOEt (150 mL) and washed with brine (30 mL×3). The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by chromatography to give title compound (1.1 g, yield 68.7%) as a yellow solid. MS: 207.9 (M+H+, 1C1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)=[O:4].C([C@@H](NC([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1NC(C1NC2C(C=1)=CC=C(C1C=CC=CC=1)C=2)=O)=O)CC(C)C)#N>>[CH3:15][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:8]=2)[CH:13]=[C:5]1[C:3]([OH:2])=[O:4]
Reactant: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccc(-c3ccccc3)cc2[nH]1
Reactant: COC(=O)c1cc2ccc(Br)cc2n1C
Product: Cn1c(C(=O)O)cc2ccc(-c3ccccc3)cc21

Procedure:
Similarly, 1-methyl-6-phenyl-1H-indole-2-carboxylic acid was prepared from 6-bromo-1-methyl-1H-indole-2-carboxylic acid methyl ester and was used to prepare 6-Phenyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide.
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:38][C:39]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:40])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC#N
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2O3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3H in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample 1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:36])[C:23]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[N:24][O:25][C:26](=[O:30])[CH:27]([Cl:29])[Cl:28])[C:19](=[O:37])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:36])[C:23](=[N:24][O:25][C:26](=[O:30])[CH:27]([Cl:29])[Cl:28])[C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:19](=[O:37])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3cccs3)[C@H]2SC1
Yield: 53 %

Procedure:
A solution of t-butyl 3-acetoxymethyl-7β-[2-dichloroacetoxyimino-(thien-2-yl)acetamido]ceph-3-em-4-carboxylate (syn-isomer) in anisole (20 ml.) was treated with trifluoroacetic acid (100 ml.). After 5 minutes at 20° the solution was concentrated under reduced pressure at 35°. Ethyl acetate was added and the solution was again concentrated, whereupon a solid separated out. Ethyl acetate was evaporated from the residue three more times and the solid was collected and washed with ether to give 3-acetoxymethyl-7β-[2-dichloroacetoxyimino-2-(thien-2-yl)acetamido]ceph-3-em-4-carboxylic acid (syn-isomer) (37 g., 53%) λmax. (ethanol) 263 nm (ε14,800), τ(DMSO-d6) values include -0.19 (doublet, J 8 Hz; NH), 3.02 (singlet, CHCl2), 7.94 (singlet, OCOCH3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CCOCC>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1)(=[O:22])=[O:21]
Reactant: OCCCCCCCC1=CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCC1=CC1
Temperature: 0 °C

Procedure:
A solution of 3.8 mmol of 1-(7-hydroxyheptyl)-cyclopropene in 50 ml of ether was cooled in an ice bath. Triethylamine (1 ml) and 0.48 g of methanesulfonyl chloride (4.2 mmol) were added and the reaction mixture was stirred for 2½ hours at 0° C. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 1-(7-methanesulfonyloxyheptyl)-cyclopropene which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.Cl.[F:20][C:21]1([F:26])[CH2:24][CH:23]([NH2:25])[CH2:22]1>ClCCl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:25][CH:23]1[CH2:24][C:21]([F:26])([F:20])[CH2:22]1)=[O:7]
Reactant: NC1CC(F)(F)C1
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC(F)(F)C1)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
3-(Chloromethyl)benzoyl chloride (13.93 mmol, 2.63 g) was stirred in dichloromethane (50 ml) at 0° C. Triethylamine (41.8 mmol, 5.81 ml, 4.23 g) and 3,3-difluorocyclobutanamine hydrochloride (13.93 mmol, 2 g) were combined in dichloromethane and added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (3.33 g). MS (ESI) m/z 260.3 [M+H]+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:22]3[NH:23][C:19]([CH:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=4)[CH2:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[CH:20][CH:21]=3)[CH:29]=2)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(C=O)ccn3)[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2ccnc(-c3ccc(C(CC4CCOCC4)c4ccc(S(C)(=O)=O)cc4)[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-4-carbaldehyde (170 mg) in 1,2-dichloroethane (5 mL) was added 1-acetylpiperazine (115 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (250 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (180 mg, yield 85%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (19:1, volume ratio). MS: 551 (MH+).