Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].[Cl:35][C:36]1[CH:37]=[N:38][C:39](I)=[N:40][CH:41]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>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].O.CN(C)C=O>[Cl:35][C:36]1[CH:37]=[N:38][C:39]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[CH2:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[C:7]([CH3:21])[CH:8]=2)=[N:40][CH:41]=1
Reactant: Clc1cnc(I)nc1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(Cl)cn3)cc2C)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (7.85 g) obtained in Example 1, step F, 5-chloro-2-iodopyrimidine (4.35 g), tris(dibenzylideneacetone)dipalladium (0.753 g), 2,6-dimethoxy-2′-(dicyclohexylphosphino)biphenyl (1.35 g), cesium carbonate (16.08 g), dimethylformamide (65.8 mL) and water (16.5 ml) was stirred at 60° C. for 24 hr under a nitrogen atmosphere. The reaction mixture was added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) and washed with diethyl ether to give the title compound (4.61 g).
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.S1C=CC=C1S(Cl)(=O)=O>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (256 mg, 1.1 mmol) and 2-thienylsulfonyl chloride (206 mg, 1.1 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with EtOAc, to give benzamide I-4 (318 mg, 75%) as a white powder: mp (EtOAc) 185-188° C.; 1H NMR δ 10.38 (s, 1H, NHCO), 8.93 (d, J=2.2 Hz, 1H, H-2″), 8.46 (br s, 1H, NHSO2), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6″), 8.19 (ddd, J=8.2, 2.5, 1.5 Hz, 1H, H-4″), 7.90-7.95 (m, 3H, H-2, H-6, H-5′), 7.61 (dd, J=3.7, 1.3 Hz, 1H, H-3′), 7.43 (br d, J=8.3 Hz, 2H, H-3, H-5), 7.39 (ddd, J=8.2, 4.7, 0.5 Hz, 1H, H-5″), 7.18 (dd, J=5.0, 3.7 Hz, 1H, H-4′), 4.17 (s, 2H, CH2N); 13C NMR δ 165.4, 144.4, 141.9, 141.5, 141.4, 135.7, 133.0, 132.4, 131.5, 127.6 (2), 127.5, 127.3 (2), 127.2, 123.4, 45.8; MS m/z 374.6 (MH+, 100%). Anal. calcd for C17H15N3O3S2: C, 54.67; H, 4.05; N, 11.25. Found: C, 55.23; H, 4.11; N, 11.32%.
Reaction SMILES: [C:1]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:12][O:11]C(C2C=CC=CC=2)[O:9][CH2:8]1)=[O:5]>C(O)C.[Pd]>[C:4]([O:6][CH:7]([CH2:12][OH:11])[CH2:8][OH:9])(=[O:5])[CH2:3][CH2:2][C:1]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C(CCC(=O)OC1COC(c2ccccc2)OC1)Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCC(=O)OC(CO)CO)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyl 2-phenyl-1,3-dioxan-5-yl succinate (0.11 g, 0.3 mmol) was dissolved in ethanol (20 ml) under argon and Pd/C (0.09 g, 0.1 mmol) was added. The flask was flushed with hydrogen and allowed to stir under 1 atm H2 at room temperature for 16 h. The crude reaction mixture was passed through a plug of celite and the solvent was removed under reduced pressure yielding (0.9 g, 0.26 mmol, 89%). The product was used without any further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:5][CH:4]=1.Cl.[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19].C(N(CC)CC)C.CCOC(C)=O>ClCCl>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:19][C@H:18]([C:17]([O:16][CH3:15])=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)CCc1ccc(CCl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
To a cooled (0° C.), stirred solution of 1.6 g (6.2 mmol) of 3-[4-(chloromethyl)phenyl]propionyl chloride and 1.3 g (6.2 mmol) of phenylalanine methyl ester hydrochloride salt in 6 ml of dichloromethane was added 1.4 g (14 mmol) of triethylamine. The reaction mixture was stirred at 0° C. for 0.5 hour, poured into EtOAc and washed with water. The EtOAc layer was dried over Na2SO4, filtered and evaporated to afford an oil. This oil was flash chromatographed (40% EtOAc/hexanes) to give 0.8 g of product; m.p. 89°-90° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[OH-:12].[Na+].[Cl-].[Na+]>O.[Cl-].[Cl-].[Zn+2]>[CH2:8]([C:7]1[C:5](=[O:6])[CH2:4][CH:3]([OH:12])[C:2]=1[CH3:1])[CH2:9][CH3:10]
Reactant: Cc1ccc(CCCCO)o1
Reactant: [OH-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: CCCC1=C(C)C(O)CC1=O

Procedure:
In a reaction vessel, 5-methyl-2-furylpropylcarbinol (1 g) was charged, and a solution of ZnCl2 (0.9 g) in water (40 ml) was added. The temperature was elevated up to 100° C. to reflux, and several drops of an aqueous 0.1N NaOH solution were added thereto to adjust the pH value to 4.5. By further addition of the same NaOH solution (0.3 ml) thereto, the pH value was not changed but remained at 4.5. The mixture was stirred under reflux for 11 hours, whereby the pH value became 4.2. After cooling, sodium chloride (12 g) was added thereto, and the mixture was extracted with toluene (30 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove toluene, and the resultant residue was subjected to chromatography with silica gel (10 g) and a mixture of ethyl acetate-n-hexane (1:2 by volume) as the developing solvent to obtain 2-propyl-3-methyl-4-hydroxy-2-cyclopentenone (0.57 g). Yield, 57%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[N:21]=[C:20]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=[C:18]([C:30](=[NH:33])[NH:31]O)[N:17]=1.NC1N=C(N(C)C2C=CC=C(C)C=2)N=C(C(NO)=N)N=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:10][N:33]=[C:30]([C:18]3[N:19]=[C:20]([N:22]([CH3:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[C:16]([NH2:15])[N:17]=3)[N:31]=2)=[CH:4][CH:3]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(C(=N)NO)n1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(Cl)nc3)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Chloropyridine-3-carboxylic acid (Ig, 6.35 mmol) and thionyl chloride (10 mL, 138 mmol) were heated to reflux for 2 hours. The mixture was concentrated under vacuum and the residue was azeotroped with diethyl ether and evaporated. A portion of this acid chloride (0.75 g, 4.26 mmol) was then added to a solution of 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1, 0.920 g, 3.55 mmol) in pyridine (12 mL) and the mixture was stirred at room temperature overnight before being heated to 70 C for 3 h. The mixture was cooled to room temperature and concentrated under vacuum. Water was added and the mixture was stirred for 30 min. The solids were filtered and washed with further water. The solid was then azeotroped with toluene and dried under vacuum to afford the title compound, which was used without purification in the next step. Method B HPLC-MS: MH+ requires m/z=381 Found: m/z=381, Rt=1.99 min (35%).
Reaction SMILES: [O:1]1[CH:15]2[CH:2]1[C:3](=[O:25])[C@@H:4]([C@H:14]2/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[C:32]([O:24][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:17]=[CH:16]/[C@@H:14]1[C@@H:4]([CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:3](=[O:25])[CH:2]2[O:1][CH:15]12)(=[O:34])[CH3:33]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C2OC2C(=O)[C@@H]1C/C=C\CCCC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCCC[C@@H](/C=C/[C@H]1C2OC2C(=O)[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Reaction time: 18 h

Procedure:
to a solution of 1 part of (5Z,13E,15S)-10ξ,11ξ-epoxy-15-hydroxy-9-oxoprosta-5,13-dien-1-oic acid in 30 parts of pyridine at 5° is added 10 parts of acetic anhydride. The resultant mixture is allowed to stand at 5° for 18 hours, whereupon it is poured into 10 volumes of water. The mixture thus obtained is allowed to stand for 1 hour, then extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual red oil is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 20% ethyl acetate in benzene, on evaporation of solvent, (5Z,13E,15S)-15-acetoxy-10ξ,11ξ-epoxy-9-oxoprosta-5,13-dien-1-oic acid is obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].OS(O)(=O)=O.[CH3:21]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C(=O)CCC(=O)O)ccc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(F)c(C)c1
Reaction time: 16 h

Procedure:
To a solution of 4-(4-fluoro-3-methylphenyl)-4-oxobutanoic acid in 30 mL methanol was added concentrated H2SO4 (300 mL) at room temperature and the resulting mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue treated with 30 mL water and the resulting mixture extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×20 mL) and dried over Na2SO4. The product was isolated by flash column chromatography eluting with 0% to 10% ethyl acetate/hexane gradient solvent to give 568 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:15][C:16]#[C:17][C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3].CS(C(CC#C[C@H](O)CCCCC)CCCCCCC(O)=O)(=O)=O>>[CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][C@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Agent: CCCCC[C@@H](O)C#CCC(CCCCCCC(=O)O)S(C)(=O)=O
Product: CCCCC[C@@H](O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out by the procedure described in Example 15 except that the 8-methylsulfonyl-12(S)-hydroxy-10-heptadecynoic acid is replaced by an equivalent quantity of 8-methylsulfonyl-12(R)-hydroxy-10-heptadecynoic acid.
Reaction SMILES: [CH2:1]=[CH:2]C(=C)C.[CH3:6][O:7][C:8]([O:12][CH2:13][C:14]#[CH:15])([CH2:10][CH3:11])[CH3:9].BrCC>CCCCCC>[CH3:6][O:7][C:8]([CH3:9])([O:12][CH2:13][C:14]#[C:15][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: C=CC(=C)C
Reactant: C#CCOC(C)(CC)OC
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC(C)(CC)OC
Temperature: -38 °C
Reaction time: 0.42 h
Yield: 89.1 %

Procedure:
890 mg (127 mmol) of granulated lithium were added within 5 minutes to 100 ml (4.0 mol) of liquid ammonia at −40° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 5.94 g (86.6 mmol) of isoprene was added portion wise within 10 minutes, whereas the solution gets white at the end of the addition. The mixture was stirred for 25 minutes at −38° C. 9.1 g (69.5 mmol) of 2-methoxy-2-prop-2-ynyloxy-butane (97.4% GC) were added with a dropping funnel to the reaction mixture at −38° C. within 25 minutes. The reaction mixture was held at −38° C. for about 1 hour. 14 g (128.5 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1 hour and 30 minutes. 50 ml of water was added to the reaction mixture at 40° C., and the mixture was stirred until all salt was dissolved. The mixture is transferred into a separatory funnel and the layers were separated. The aqueous layer is extracted with 127 ml of n-hexane. The organic layers were dried over 0.5 g of anhydrous sodium sulphate and concentrated under reduced pressure (40° C., 60 mbar), and the crude product (1-(1-methoxy-1-methyl-propoxy)-pent-2-yne) was analyzed by GC. 10.54 g of crude 1-(1-methoxy-1-methyl-propoxy)-pent-2-yne were obtained with a purity of 87.1% (yield 77.6% based on 2-methoxy-2-prop-2-ynyloxy-butane).
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(O)(=O)C.C(O[C:35]1(O[Si](C)(C)C)[CH2:37][CH2:36]1)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][N:19]([CH:35]2[CH2:37][CH2:36]2)[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C(CNc1ccc(O)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(CN(c1ccc(O)cc1)C1CC1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-piperonylpiperazin-1-yl)-2-(4-hydroxyphenylamino)ethanone (1.00 g, 2.7 mmol) in methanol (10 mL) were added acetic acid (1.55 mL, 27 mmol), molecular sieves 3A1/16 (1.00 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.653 mL, 3.2 mmol) and sodium cyanoborohydride (770 mg, 12 mmol). The resulting solution was stirred for 16 hours at 60° C. This reaction solution was filtered and concentrated, and to the residue were added ethyl acetate and water. The aqueous layer was adjusted to pH 10 using aqueous 6 N sodium hydroxide. This layer was stirred for some time, and once insoluble matter had dissolved, the ethyl acetate layer was removed, and washed with aqueous 2 N sodium hydroxide and a saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulfate. The solvent was evaporated, to thereby yield 770 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:44]#[N:45])=[C:27]([C:29]2[C:34]([O:35][CH3:36])=[CH:33][N:32]([CH:37]([CH2:41][CH3:42])[C:38](O)=[O:39])[C:31](=[O:43])[CH:30]=2)[CH:28]=1.C(OC)(C)(C)C>CN(C)C=O.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:44]#[N:45])=[C:27]([C:29]2[C:34]([O:35][CH3:36])=[CH:33][N:32]([CH:37]([CH2:41][CH3:42])[C:38]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)=[O:39])[C:31](=[O:43])[CH:30]=2)[CH:28]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C(CC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
Under argon and at RT, 476 mg (2.9 mmol, 1.0 eq.) of ethyl 4-aminobenzoate and 41 mg (0.29 mmol, 0.1 eq.) of Oxima and then, dropwise, 452 μl (2.9 mmol, 1.0 eq.) of N,N′-diisopropylcarbodiimide (DIC) were added to a solution of 1.0 g (2.9 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) in 10 ml of dimethylformamide. The reaction mixture was stirred at 40-45° C. for 3 h and cooled to RT, methyl tert-butyl ether and water were added and the mixture was stirred vigorously for 10 min, resulting in the formation of a precipitate. The precipitate was filtered off, washed twice with water and methyl tert-butyl ether and dried under reduced pressure (precipitate 1). After phase separation of the combined filtrates, the aqueous phase was extracted once with methyl tert-butyl ether. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether, filtered, washed twice with methyl tert-butyl ether and dried under reduced pressure. This precipitate was stirred in aqueous hydrochloric acid (1N) for 10 min, filtered off, washed twice with water and once with acetonitrile and dried under reduced pressure (precipitate 2). Yield: precipitate 1: 1.12 g (79% of theory), precipitate 2: 127 mg (still contains 1,3-diisopropylurea according to 1H NMR)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH:11]([F:13])[F:12])[CH:3]=1.[NH4+].[Cl-]>C(O)C.O.C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH:11]([F:12])[F:13])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc(C(F)F)c1
Temperature: 95 °C
Yield: 82.1 %

Procedure:
Iron (1.99 g, 35.7 mmol) was added to a vigorously stirred mixture of 1-bromo-3-(difluoromethyl)-5-nitrobenzene (1.80 g, 7.14 mmol) and NH4Cl (0.191 g, 3.57 mmol) in ethanol (30 mL) and water (15 mL). The mixture was heated to 95° C. for 2 h. It was then diluted with ethyl acetate while still hot and filtered over Celite. The filtrate was washed with dilute aqueous NaHCO3 and brine. After solvent evaporation the residue was purified through a silica plug, eluting with 1:5 ethyl acetate:hexanes to yield 3-bromo-5-(difluoromethyl)aniline (1.3 g, 5.86 mmol, 82%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([CH3:21])[CH:12]=3)=[CH:4][CH:3]=1.Cl.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][O:20][C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH3:21])[CH:12]=3)[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH3:26]
Reactant: Cc1ccc2c(c1)c1c(O)cccc1n2Cc1ccc(F)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cc(C)ccc1n2Cc1ccc(F)cc1
Yield: 48.3 %

Procedure:
9-(4-Fluorobenzyl)-6-methyl-9H-carbazol-4-ol (0.0505 g, 0.17 mmol), 2-diethylaminoethylchloride hydrochloride (0.0411 g, 0.24 mmol), potassium carbonate (0.1018 g, 0.74 mmol), sodium iodide (0.0046 g, 0.031 mmol) and DMF (3 mL) are heated at 85° C. for 3 h. After the mixture had cooled, it is partitioned between water and ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated to dryness. The residue is chromatographed on silica gel (60 mL) using methanol/dichloromethane (1/99 to 2/98 to 4/96) to give 0.0332 g (50%) of the title compound; MS (ESI+) for C26H29FN2O m/z 405.3 (M+H)+; IR (drift) 2966, 1601, 1506, 1460, 1339, 1269, 1242, 1218, 1150, 1127, 1054, 790, 781, 746, 717 cm−; 1H NMR (CDCl3) δ1.90, 2.55, 2.80, 3.18, 4.39, 5.46, 6.71, 6.94, 7.07, 7.22, 7.33, 8.19. Anal. Calcd for C26H29FN2O: C, 77.20; H, 7.22; N, 6.93. Found: C, 75.79; H, 7.61; N, 6.55.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3CC[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4NC(=O)C)[CH2:13]3)[C:6]=2[N:7]=1.C(Cl)Cl.[CH3:35][OH:36]>>[Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:36][CH3:35])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1
Reactant: CC(=O)Nc1cccc2c1CCN(c1ncnc3c(N4CCOCC4)nc(Cl)nc13)C2
Reactant: CO
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1

Procedure:
2-chloro-8-(5-acetylamino-1,2,3,4 -tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido [5,4-d]pyrimidine Rf value: 0.55 (silica gel; methylene chloride/methanol=9:1)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=3)=[N:9][CH:10]=2)[CH2:2]1.[O:21]1[CH2:24][C:23](=O)[CH2:22]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:18][C:16]1[CH:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH:3]3[CH2:4][N:1]([CH:23]4[CH2:24][O:21][CH2:22]4)[CH2:2]3)=[CH:10][N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: O=C1COC1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(C3CN(C4COC4)C3)cn2)c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 239b (140 mg, 0.42 mmol), oxetan-3-one (91 mg, 1.26 mmol), NaBH3CN (78 mg, 1.26 mmol), and zinc chloride (171 mg, 1.26 mmol) in methanol (10 mL) was stirred at 50° C. for 2 hours. The mixture was concentrated under reduced pressure and water (5 mL) was added to the residue. It was then extracted with dichloromethane (3×10 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50:1 dichloromethane/methanol to afford 272a (145 mg, 85%). MS-ESI: [M+H]+ 390.8
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.S([N:32]=[N+:33]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[N+:32](=[C:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][C:11]1=[O:13])=[N-:33]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)CC(c2ccccc2)CC1=O
Yield: 36.9 %

Procedure:
A solution of 20.0 g (0.106 mol) of 5-phenylcyclohexane-1,3-dione in 75 ml ethanol was cooled to -10° C. and stirred magnetically under nitrogen. To the mixture was added 10.75 g (0.106 mol) of triethylamine. The tosyl azide (20.95 g 0.106 mol) was added all at once, and the mixture stirred for one hour at 0°-5° C. The solvent was removed under vacuum at a temperature less than 40° C. To the residue was added 200 ml ether, and the mixture extracted with a solution containing 3.1 g potassium hydroxide in 200 ml of water. The ethereal solution was dried over anhydrous MgSO4 filtered and the solvent removed to give a yellow solid which was recrystallized from ethanol-hexane to give 8.38 g (32%) of 2-diazo-5-phenylcyclohexane-1,3-dione as yellow crystals, mp 122°-124 ° C.