Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C[O:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14](I)[CH:13]=[C:12](Br)[CH:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@:26]2([CH:38]([CH3:40])[CH3:39])[C@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@@:26]2([CH:38]([CH3:40])[CH3:39])[C@@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:12]4[CH:11]=[C:10]([CH:15]=[C:14]([N:3]5[CH2:4][CH2:5][O:1][C:2]5=[O:6])[CH:13]=4)[C:9]([OH:8])=[O:18])[C:29]3=[O:37])[CH2:27]2)=[CH:24][CH:25]=1
Reactant: CC(C)[C@]1(c2ccc(Cl)cc2)C[C@]12C(=O)Nc1ccccc12
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: O=C1NCCO1
Product: CC(C)[C@@]1(c2ccc(Cl)cc2)C[C@@]12C(=O)N(c1cc(C(=O)O)cc(N3CCOC3=O)c1)c1ccccc12

Procedure:
The title compound was prepared in analogy to Example 95 starting from oxazolidin-2-one, 3-bromo-5-iodobenzoic methylester (prepared as in Example 92), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)-2-isopropylspiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 2. LC/MS m/e calcd. for C29H25ClN2O5: 516, observed (M+H)+: 517.2 1H NMR (400 MHz, DMSO-d6) δppm 0.77 (d, 3 H) 0.89 (d, 3 H) 2.16 (d, 1 H) 2.28 (d, 1 H) 2.95-3.02 (m, 1 H) 4.17-4.25 (m, 2 H) 4.40-4.58 (m, 2 H) 5.43 (d, 1 H) 6.65-6.76 (m, 1 H) 6.78-6.91 (m, 2 H) 7.11 (t, 1 H) 7.61 (d, 1 H) 7.69 (d, 1 H) 7.79 (s, 1 H) 7.92-8.03 (m, 2 H) 8.21 (s, 1 H) 13.44 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>C(N(CC)CC)C.CN(C)C=O>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a mixture of 3-methyl-1-benzofuran-2-carboxylic acid (15.0 g), N,O-dimethylhydroxyamine hydrochloride (9.95 g), 1-hydroxybenzotriazole-monohydrate (15.6 g), triethylamine (14.2 mL) and N,N-dimethylformamide (150 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.6 g), and the mixture was stirred overnight at room temperature. In addition, N,O-dimethylhydroxyamine hydrochloride (4.16 g), 1-hydroxybenzotriazole-monohydrate (6.52 g), triethylamine (5.94 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.17 g) were added, and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7, volume ratio) to give the title object compound (16.2 g, 87%) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][C@@H:27]([CH3:44])[CH2:28][N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:41]=[C:40]([F:42])[C:37]([C:38]#[N:39])=[C:36]([Cl:43])[CH:35]=2)=[N:30]1.C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:26][C@@H:27]([CH3:44])[CH2:28][N:29]2[CH:33]=[CH:32][C:31]([C:34]3[CH:41]=[C:40]([F:42])[C:37]([C:38]#[N:39])=[C:36]([Cl:43])[CH:35]=3)=[N:30]2)=[O:10])[CH:4]=1
Reactant: O=C(O)c1cc(CBr)on1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
5-(Bromomethyl)isoxazole-3-carboxylic acid (0.718 mmol, 0.148 g) was dissolved in DCM (5 ml) and THF (1 ml). 1,3-Dicyclohexylcarbodiimide (0.718 mmol, 0.148 g) was added and the resulting mixture was stirred at RT. The precipitate formed was filtered and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.359 mmol, 0.1 g), triethylamine (0.359 mmol, 0.036 g) and dry DCM (5 ml) was added to the filtrate. The filtrate was stirred at RT under nitrogen atmosphere for two days during which more 1,3-dicyclohexylcarbodiimide (0.148 g), triethylamine (0.050 ml) and 5-(bromomethyl)isoxazole-3-carboxylic acid (0.1 g) were added. The reaction mixture was diluted with DCM and washed with NaHCO3. The organic phase was dried, filtered and evaporated. The crude product was purified with flash chromatography. 0.064 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, 3H), 4.00-4.09 (m, 2H), 4.23-4.31 (m, 1H), 4.41-4.48 (m, 1H), 4.53-4.63 (m, 1H), 6.60-6.66 (m, 1H), 6.74-6.78 (m, 1H), 7.48-7.53 (m, 1H), 7.64 (d, 1H), 7.79-7.88 (m, 2H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13](=[O:14])[NH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:7]=1.CO[C:20]1[N:25]=[C:24]([C:26]([O-])=O)C=C[C:21]=1N1C=C(C)N=C1>Cl.O1CCOCC1>[Cl:1][CH2:21][CH2:20][N:25]1[CH2:24][CH2:26][N:12]2[C:13](=[O:14])[C:8]([N:6]3[CH:7]=[C:3]([CH3:2])[N:4]=[CH:5]3)=[CH:9][CH:10]=[C:11]2[C:15]1=[O:17]
Reactant: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Reactant: COc1nc(C(=O)[O-])ccc1-n1cnc(C)c1
Reactant: Cl
Solvent: C1COCCO1
Product: Cc1cn(-c2ccc3n(c2=O)CCN(CCCl)C3=O)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Synthesis of 5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid, hydrochloride salt (C3). A solution of 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylate (C2) (34.3 g, 139 mmol) in aqueous hydrochloric acid (37%, 230 mL) and 1,4-dioxane (230 mL) was heated at reflux for 18 hours. After cooling to room temperature, the reaction was filtered and the solids were washed with 1,4-dioxane (2×100 mL). The solids were mixed with methanol (500 mL) and the volatiles were removed in vacuo. The residue was stirred with methanol (100 mL) for 15 minutes, and 1,4-dioxane (250 mL) was added. The resulting mixture was stirred for 15 minutes; the solids were collected by filtration and washed with 1,4-dioxane to provide the title compound as a beige solid. Yield: 35.4 g, 138 mmol, 99%. 1H NMR (300 MHz, DMSO-d6) δ 2.33 (d, J=0.9 Hz, 3H), 7.09 (d, J=7.5 Hz, 1H), 7.84-7.87 (m, 1H), 8.04 (d, J=7.5 Hz, 1H), 9.50 (d, J=1.6 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl[CH2:25][O:26][CH2:27][CH3:28]>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:27]([O:26][CH2:25][N:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:11])[NH:6][C:7]1=[O:10])[CH3:28]
Reactant: CC(C)c1c[nH]c(=O)[nH]c1=O
Reactant: CCOCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [I-]
Solvent: ClCCl
Product: CCOCn1cc(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-isopropyluracil (18 g) in dichloromethane (230 ml) was added bis-trimethylsilylacetamide (60.7 ml) and the mixture stirred for 1 hr at room temperature. To the solution were added tetra-n-butylammonium iodide (0.46 g) and chloromethylethyl ether (10.7 ml) at room temperature and the mixture stirred for 1.5 hr. The resultant mixture was washed and partitioned with cooled water (50 ml) (×2). The organic layer was concentrated under reduced pressure. The residue was crystallized at room temperature from n-heptane (100 ml) to yield 1-ethoxymethyl-5-isopropyluracil (22.2 g). M.p., 78.4° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([F:36])[CH2:12][N:11]([C:13](=[O:35])/[CH:14]=[CH:15]\[N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)=[N:17]2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1([F:36])[CH2:12][N:11]([C:13](=[O:35])/[CH:14]=[CH:15]\[N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=3)=[N:17]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.3 %

Procedure:
(Z)-tert-Butyl(1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidin-3-yl)methylcarbamate (0.15 g, 0.279 mmol) was dissolved in DCM (10 mL) and TFA (0.1 mL) was added at 0° C. The reaction mixture was stirred at rt for 4 h and concentrated under reduced pressure to afford 0.5 g of crude product, which was purified by chromatography (0-5% methanol in DCM) to afford 15 mg of (Z)-1-(3-(aminomethyl)-3-fluoroazetidin-1-yl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)prop-2-en-1-one (Yield 15%). 1H NMR (400 MHz, CDCl3, ppm) δ=9.4 (s, 1H); 8.54 (s, 2H); 8.32 (s, 1H); 8.13 (s, 3H); 7.49-7.46 (d, J=10 Hz, 1H); 6.0-5.97 (d, J=10 Hz, 1H); 4.41-4.06 (m, 4H); 3.49-3.36 (m, 3H). LCMS calcd for C17H15F7N5O [M+H]+ 438.3. found: 438.19 (retention time 2.298 min).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]2[CH2:11][CH2:10][C@:9]3([OH:26])[C@H:12]4[C@H:22]([CH2:23][CH2:24][C@:7]23[CH3:8])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([OH:25])[CH2:18][CH2:19]2)[CH2:14][CH2:13]4)=[CH:2]1.O1[C@@H]2C[C@H](C3C=COC=3)[C@]3(CC[C@H]4[C@H]([C@@]123)CC[C@H]1[C@]4(C)CC[C@H](O)C1)C.N1C=CN=C1.[Si:58](Cl)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]>O.CN(C)C=O>[Si:58]([O:25][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@:9]3([OH:26])[CH2:10][CH2:11][C@@H:6]2[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH2:16]1)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Agent: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Yield: 113.7 %

Procedure:
To a solution of 10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc. (C), 1966, 377)in 80 ml of dimethylformamide, 18 g of imidazole and 20.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure and 15 g of crude 3β-tert-butyldimethylsilyloxy-17β-(3-furyl)-5β-androstan-14β-ol were obtained. A suspension of this protected alcohol and 1.3 g of KH in 75 ml of tetrahydrofuran was heated at 70° C. for an hr; then 2.7 g of methyl iodide were added. After 30' the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 12 g of 3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5β-androstane as a white amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](Cl)=[O:10])([O-:3])=[O:2].[N+:15]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].N1C=CC=CC=1>CC(C)=O>[N+:15]([C:18]1[CH:19]=[C:20]([O:24][C:9](=[O:10])[CH:8]=[CH:7][C:6]2[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1cccc([N+](=O)[O-])c1)Oc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 90.2 %

Procedure:
64.5 g (0.3 mole) of 3-nitrocinnamoyl chloride and 300 g of acetone were placed in a reaction vessel and stirred at 50° C. under a nitrogen current. 41.73 g (0.3 mole) of 3-nitrophenol, 60 g of pyridine, and 300 g of acetone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction mixtures were stirred under a nitrogen current for 2 hours. After the reaction, the solid obtained by concentrating the solution was washed by water and dried. 85 g of light yellow colored needle-like crystals ((3-nitrophenyl)-3-cinnamate) was yielded.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:5])[NH2:4].[Cl:6][C:7]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:8]=1[CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12]>>[NH2:14][CH2:13][C:10]1[C:11]([NH2:12])=[N:5][C:3]([O:2][CH3:1])=[N:4][C:9]=1[C:8]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:7]=1[Cl:6]
Reactant: COC(=N)N
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: COc1nc(N)c(CN)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
The title compound, MS: m/e=337.8 (M+), was prepared from 2-methyl-isourea and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CI.[CH3:15][N:16]([CH:18]=[O:19])C>C1COCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:16]1[CH2:15][CH2:5][CH2:4][CH2:3][CH2:2][C:18]1=[O:19]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CN(C)C=O
Solvent: CI
Solvent: C1CCOC1
Product: O=C1CCCCCN1Cc1ccc2ccccc2c1
Yield: 97 %

Procedure:
Following the procedure described in Example 122, step 1, but substituting respectively 2-bromomethylnaphthalene for methyl iodide, and DMF for THF, the title compound 217 was obtained in 97% yield. MS (ESI)=254 (MH+).
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([O:18]C)=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl.[Cl-].[Na+].O>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
A mixture of 9-fluoro-6-methoxybenzo[g]isoquinoline-5,10-dione (0.072 g) and aluminum trichloride (0.112 g) in dry methylene chloride (40 mL) is stirred at room temperature for 4 hours under a nitrogen atmosphere. An additional portion of aluminum chloride (0.190 g) is added and the mixture is allowed to react at reflux for 1.5 hrs and at room temperature overnight. Following addition of brine (15 mL) the aqueous phase is separated and extracted with methylene chloride (3×5 mL). The combined organic solutions are dried over anhydrous sodium sulphate and the solveht is removed by distillation at reduced pressure to give an approximately 1:1 mixture (0.070 g) of 9-fluoro-6-hydroxybenzo[g]isoquinoline-5,10-dione (slower moving yellow spot on silica gel TLC plate, eluant methylene chloride/ethyl acetate 70/30) and 9-chloro-6-hydroxybenzo [g]isoquinoline-5,10-dione (faster moving yellow spot on the above chromatographic system) which is used without further purification for the next step.
Reaction SMILES: ICC[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([F:27])[C:19]=1[F:28])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(C)C=CC=CC=1.O.C(O)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[C:20]([F:27])[C:19]=1[F:28])[CH3:16]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: CCOC(=O)c1ccc(CCI)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCC)c(F)c2F)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Ethyl 4-iodoethylbenzoate (1) (25.0 g), 4-ethoxy-2,3-difluorophenylboronic acid (2) (20.1 g), potassium carbonate (25.0 g), Pd/C (0.25 g), toluene (100 ml), ethanol (100 ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases. The extraction to an organic phase was carried out. The organic phase obtained was washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel; toluene). The product was further purified by means of recrystallization from ethanol and dried, giving 18.8 g of ethyl 4-ethoxy-2,3-difluoro-4′-biphenylcarboxylate (3). The yield based on the compound (1) was 67.9%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][F:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[C:34]([O:37]CC)(=[O:36])[CH3:35].Cl.[C:41]([O:44]CC)(=[O:43])[CH3:42]>CC(O)C>[C:41]([OH:44])(=[O:43])/[CH:42]=[CH:35]/[C:34]([OH:37])=[O:36].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][F:23])=[CH:20][CH:21]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(C)=O
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(CF)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(CF)o2)c(-c2cccnc2F)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of tert-butyl {[4-fluoro-1-{[5-(fluoromethyl)-2-furyl]sulfonyl}-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (165 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→ethyl acetate) to give a free base of the title compound as a colorless oil (yield 114 mg, 87%). A solution of the obtained free base (114 mg) in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (34.4 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 94.6 mg, 56%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:2]1.C[Si]([N:34]=[C:35]=[O:36])(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:29][C:22]1[C:23]([F:28])=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[CH:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][N:1]([C:35]([NH2:34])=[O:36])[CH2:4]4)[CH:9]=3)[CH:11]=2)[NH:16][CH:17]=1)[CH3:20]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CN(C(N)=O)C4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(1-azetidin-3-yl-1H-pyrazol-4-yl)-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (6.0 mg, 0.014 mmol), trimethylsilyl isocyanate (5.0 μL, 0.037 mmol), DIPEA (0.02 mL, 0.09 mmol) and DCM (2 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.89 (d, J=7.1 Hz, 3 H), 4.29-4.36 (m, 2 H), 4.42 (t, J=8.5 Hz, 2 H), 5.20-5.34 (m, 2 H), 7.14-7.23 (m, 1 H), 7.37 (d, J=1.3 Hz, 1 H), 7.39-7.52 (m, 2 H), 7.69 (s, 1 H), 7.94 (s, 1 H), 8.33 (s, 1 H). MS (ES+): m/z 473.11 (100) [MH+]. HPLC: tR=2.86 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[C:24](=[O:25])[N:23]5[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]5=[N:21][C:20]=4[CH3:31])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(O)(=O)C>[C:32]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[C:24](=[O:25])[N:23]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]4=[N:21][C:20]=3[CH3:31])[CH2:13][CH2:12]2)=[N:7]1)(=[O:34])[CH3:33]
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)n1nc(C2CCN(CCc3c(C)nc4c(C)cccn4c3=O)CC2)c2ccc(F)cc21
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of 3.2 parts of 3-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperdinyl]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 27 parts of acetic anhydride and 15.7 parts of acetic acid was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was poured into 100 parts of water. After basifying with NH4OH, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was crystallized from 2-propanol, yielding 3.3 parts (95.3%) of 3-[2-[4-(1-acetyl-6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 210.3° C. (compound 46).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([O:45]C)=O)[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.CN>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:2][CH3:1])=[O:45])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. Methylamine (2M in THF, 1.0 mL, 2.0 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was triturated with MeOH to yield a white solid (0.024 g, 46% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17]N(C)C)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:21])[O:5][N:4]=1)[CH3:2].[C-]#[N:23].[Na+].[CH2:25]([OH:27])C>O>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:25]([NH2:23])=[O:27])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:21])[O:5][N:4]=1)[CH3:2]
Reactant: [C-]#N
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1CN(C)C
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(N)=O
Reaction time: 0.5 h

Procedure:
A mixture of 24.8 g. (0.088 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-(dimethylaminomethyl)-indole and 23 g. (0.47 mole) of sodium cyanide in 175 ml. ethanol and 50 ml. water are refluxed for 80 hours. The mixture is then cooled and poured onto water, stirred for 1/2 hour and filtered to yield 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetamide; m.p. 194° to 195° C. The filtrate, which contains the sodium salt of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetic acid is evaporated to remove ethanol and acidified with cold 12 N hydrochloric acid and the precipitate filtered to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetic acid; m.p. 194° to 197° C.