Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].OS(O)(=O)=O.[Br:8][C:9]1[C:10](=O)[O:11][C:12](=[O:14])[CH:13]=1>O>[Br:8][C:9]1[C:10](=[O:11])[NH:1][NH:2][C:12](=[O:14])[CH:13]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: NN
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(Br)c(=O)[nH][nH]1
Temperature: 90 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a solution of NH2NH2.H2SO4 (362 mg, 2.8 mmol) in H2O (5 mL) was added dropwise 3-bromofuran-2,5-dione (500 mg, 2.8 mmol), and the mixture was stirred at 90° C. for 4 hours. After the reaction, the mixture was filtered to get 4-bromo-1,2-dihydropyridazine-3,6-dione (300 mg, yield: 56%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.47 (s, 1H), 11.17 (s, 1H), 7.62 (s, 1H). MS (M+H)+:191/193.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:30]1[CH:35]=[C:34]([C:36]([NH:38][C:39]2([C:42]([OH:44])=O)[CH2:41][CH2:40]2)=[O:37])[CH:33]=[N:32][CH:31]=1.[F:45][CH:46]([F:64])[O:47][C:48]1[CH:63]=[CH:62][C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]([NH2:61])[CH3:60])=[CH:55][CH:54]=2)=[CH:50][CH:49]=1>CN(C=O)C>[F:45][CH:46]([F:64])[O:47][C:48]1[CH:63]=[CH:62][C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]([NH:61][C:42]([C:39]3([NH:38][C:36]([C:34]4[CH:33]=[N:32][CH:31]=[N:30][CH:35]=4)=[O:37])[CH2:40][CH2:41]3)=[O:44])[CH3:60])=[CH:55][CH:54]=2)=[CH:50][CH:49]=1
Reactant: CC(N)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1(NC(=O)c2cncnc2)CC1)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
376 μL (2.70 mmol) of triethylamine and 0.52 g (1.62 mmol) of TBTU were added to a solution of 0.28 g (1.35 mmol) of 1-[(pyrimidin-5-carbonyl)-amino]-cyclo-propanecarboxylic acid (from 1b) in 5 mL DMF and the mixture was stirred for 5 min at RT. Then 0.42 g (1.50 mmol) of 1-[4-(4-difluoromethoxy-phenoxy)-phenyl]-ethylamine was added and the mixture was stirred for 30 min at ambient temperature. The reaction mixture was purified by chromatography (reversed phase). The acetonitrile was distilled off, the aqueous phase was made basic with ammonia and extracted with dichloromethane. The organic phase was dried and evaporated down.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (0.8 g) and N,N-dimethylformamide (25 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.25 g, 86%).
Reaction SMILES: CO[CH:3]([O:12]C)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][N:5]=1.[S-2:14].[Na+].[Na+]>O>[CH:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:14][S:14][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:12])=[N:5][CH:6]=2)=[CH:6][N:5]=1)=[O:12]
Reactant: [S-2]
Reactant: COC(OC)c1ccc(CCl)cn1
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(CSSCc2ccc(C=O)nc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.1 mole of 2-di(methoxy)methyl-5-chloromethylpyridine in absolute alcohol (150 ml.) is added dropwise at 10°-15° C. over 20 minutes, to a suspension of 6 g. of sodium sulfide (Na2S2) in 50 ml. of absolute alcohol. The mixture stirred at room temperature for 1/2 hour, then 15 min. at 40°-50° C. and poured into 800 ml. of water. The mixture is extracted with ether and the extract is dried over magnesium sulfate and concentrated to an oil. The oil is dissolved in 80 ml. of 1 N hydrochloric acid and heated for 2- min. at 40° C. The mixture is cooled, adjusted to pH 7 with sodium bicarbonate and extracted with ethylacetate. The extract is dried over magnesium sulfate and concentrated to dryness to give bis[2-formyl-5-pyridylmethyl]disulfide.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.Cl>C1C=CC=CC=1>[CH3:21][S:22]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:24])=[O:23]
Reactant: CCCCC(CO)c1ccccc1Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCC(COS(C)(=O)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Into a 500 ml round bottom flask are placed 15.6 g (0.06 mole) of 2-(o-phenoxyphenyl)hexan-1-ol, in 100 ml of benzene and 7.9 g. (0.07 mole) of methane sulfonyl chloride. To this mixture is added 8.2 g (0.08 mole) of triethyl amine dropwise at 10°. The reaction mixture is stirred overnight at room temperature and poured into 150 ml 10% hydrochloric acid. It is then extracted with benzene and the combined benzene extracts are washed with water and dried over Na2SO4. Solvent is evaporated to give 20 g of product.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]=2[CH:18]=1.[Br:19][Si](C)(C)C>C(Cl)(Cl)Cl>[Br:19][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]=2[CH:18]=1
Reactant: COCCCN1C(=O)COc2ccc(CO)cc21
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: COCCCN1C(=O)COc2ccc(CBr)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 74.0 g of 6-hydroxymethyl-4-(3-methoxy-propyl)-4H-benzo[1,4]oxazin-3-one (from example 1 g) in 600 ml of chloroform are added 58 ml of bromotrimethylsilane at room temperature. The reaction mixture is stirred for 30 minutes and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as an off white solid. Rf=0.46 (EtOAc-heptane 1:1); Rt=4.03.
Reaction SMILES: N(C(C)C)(C(C)C)CC.[Cl:10][C:11]1[C:12]([CH:17]([NH2:34])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1.[CH:35]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH:17]([NH:34][C:39]([CH:35]2[CH2:38][CH2:37][CH2:36]2)=[O:40])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of NEt(iPr)2 (150 μL, 111 mg, 0.861 mmol), DMAP (5 mg, 0.04 mmol), and C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (202 mg, 0.583 mmol) in dry CH2Cl2 (5 mL), cooled by ice/water, is added cyclobutanecarbonyl chloride (75 μL, 78 mg, 0.66 mmol), then the cooling bath is removed, and the reaction mixture is stirred at rt for 3 h. Water is added, the layers are separated, and the aqueous layer is extracted with CH2Cl2 (3×15 mL). The combined CH2Cl2 layers are washed with water, saturated NaHCO3 solution, and brine, dried over MgSO4, filtered and concentrated to give crude material as yellow foam, which is used for the next step without purification. 1H NMR (CDCl3, 400 MHz) δ 1.81-1.90 (m, 1H), 1.90-2.02 (m, 1H), 2.11-2.23 (m, 2H), 2.23-2.35 (m, 2H), 3.12 (quint, J=8.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.43-7.48 (m, 1H), 7.48-7.54 (m, 2H), 7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.90 (d, J=0.8 Hz, 1H), 8.07-8.12 (m, 2H), 8.19 (d, J=8.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H). MS (ES+): m/z 429.0/431.0 (38/13) [MH+], 469.8/471.8 (6/2) [MH++MeCN]. HPLC: tR=3.6 min (MicromassZQ, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[N:22][NH:23][CH:24]=1)=[CH:16][CH:15]=3.[H-].[Na+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2[C:35](=CC=CC=2)[O:34][CH2:33]1.COCBr>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[N:22][N:23]([CH2:33][O:34][CH3:35])[CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4c[nH]nn4)ccc3n(C)c21
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Agent: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
209 mg (0.49 mmol) of compound from Example 47, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-[1,2,3]triazol-4-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of DMF. 30 mg (0.74 mmol) of 60% NaH and a spatula tip of dibenzo-18-crown-6 are added. 80 μl of bromomethyl methyl ether are then added. The mixture is stirred at ambient temperature for 16 hours. The reaction medium is poured into water and then extracted with EtOAc and the organic phase is dried over MgSO4, filtered and evaporated to dryness, adsorbing onto silica. Purification is carried out on a silica column, elution being carried out with a gradient of EtOAc/50% cyclohexane, then with EtOAc/40% cyclohexane and, finally, 100% EtOAc. The residue is triturated in MeOH so as to obtain a beige solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[CH3:32])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[S:43])[C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[CH3:32])=[CH:4][CH:3]=1
Reactant: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1ccc(Cl)nc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=S)NCc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
To the stirred solution of (E)-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100° C. for 1 h, then cooled to ambient temperature and concentrated under reduced pressure to provide crude compound. The crude product was purified by preparative HPLC to afford the product as yellow color solid (0.03 g, 49%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:11][CH:10]=3.[F:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:23]1[C:22]([C:12]2[CH:13]=[C:14]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[CH:32][N:31]=[C:30]([F:29])[CH:35]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1ccnc(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 110 °C
Yield: 74.5 %

Procedure:
A vial was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (104.72 mg, 0.264 mmol), 2-fluoropyridin-4-ylboronic acid (74.4 mg, 0.528 mmol), potassium phosphate (168 mg, 0.792 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (9.34 mg, 0.013 mmol). The vial was flushed with Argon, then dioxane (990 μL) and water (330 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (30-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (90 mg) as a light-yellow solid. MS m/z=458.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.[Li]CCCC.[Sn:28](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32]>C(OCC)C.O>[CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][C:12]([Sn:28]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:29][CH2:30][CH2:31][CH3:32])=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2ncnn2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To. a solution of 2-benzyloxymethyltetrazole (1 mmole) and TMEDA (2 mmole) in 3 mL diethyl ether at −78° C. was added n-BuLi in hexanes (1 mmole). This was let stir for 5 min at −78° C. and then it was added to a precooled (−78° C.) solution of (n-Bu)3SnCl (1 mmole) in 2 mL of diethyl ether. After stirring at −78° C. for 30 min it was diluted with water and diethyl ether. Extraction and chromatography provided 2-benzyloxymethyl-5-(tributylstannyl)tetrazole as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Mn]([O-])(=O)(=O)=[O:19].[K+].CO>CC(C)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:19])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reaction time: 3 h
Yield: 61.6 %

Procedure:
50 g of N-ethylcarbazole-3-carboxaldehyde was dissolved in 1 L of acetone, and the solution was added with 70.6 g of potassium permanganate under ice cooling, stirred for 3 hours, then added with 100 mL of methanol and filtered. The filtrate was evaporated under reduced pressure, and the residue was dissolved in aqueous sodium hydrogencarbonate. Then, the solution was made acidic by adding concentrated hydrochloric acid, and the deposited precipitates were collected to obtain 33 g of N-ethylcarbazole-3-carboxylic acid.
Reaction SMILES: C=O.[CH:3]([CH:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]([O:8][CH3:9])=[O:7])=O>CO.C(O)(=O)C.CNC>[C:6]([O:8][CH3:9])(=[O:7])[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH2:3]
Reactant: COC(=O)CC(C=O)C(=O)OC
Agent: C=O
Agent: CNC
Solvent: CC(=O)O
Solvent: CO
Product: C=C(CC(=O)OC)C(=O)OC
Temperature: 50 °C
Reaction time: 7 h
Yield: 96.5 %

Procedure:
60 g of paraformaldehyde are added to a solution of 6.0 g of acetic acid and 6.75 g of dimethylamine in 800 g of methanol, after which 348 g of dimethyl 2-formylsuccinate are added dropwise in the course of 20 minutes. The mixture is stirred for 7 hours at 50° C. and allowed to cool, and methanol and methyl formate are distilled off. The residue is taken up in ethyl acetate and the solution is washed with 100 g of 10% strength sulfuric acid and distilled. 305 g of isomer-free dimethyl itaconate of boiling point 42°-43° C. under 0.3-0.4 mbar are obtained, corresponding to a yield of 96.4% of theory.
Reaction SMILES: Cl.[NH2:2][OH:3].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20](=O)[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C@@H:14]([C:34]([O:36][CH3:37])=[O:35])[CH2:13]1>N1C=CC=CC=1.O>[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20](=[N:2][OH:3])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C@@H:14]([C:34]([O:36][CH3:37])=[O:35])[CH2:13]1
Reactant: NO
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(=NO)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 7.6 %

Procedure:
0.32 g of hydroxylamine hydrochloride is added, with stirring and under an inert atmosphere, to a mixture of 1.27 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 13 cm3 of pyridine at a temperature in the region of 20° C. The mixture is stirred for 1 hour at a temperature in the region of 20° C. The resulting reaction mixture is diluted with 130 cm3 of distilled water and the mixture thus obtained is extracted with 50 cm3 of ethyl acetate and then two times with 30 cm3 of ethyl acetate. The combined organic phases are washed two times with 50 cm3 of distilled water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under a pressure of 50 kPa of nitrogen on a column of silica gel (particle size 20-45μ; weight of silica 160 g, diameter of the column 3.5 cm), elution being carried out with a mixture of ethyl acetate and cyclohexane (90/10 by volume). Fractions 20 to 22 are combined and then concentrated to dryness under the above conditions. 0.1 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-hydroxyimino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate is obtained.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[NH:5][C:6]=1[I:7].[H-].[Na+].[C:13]([NH:20][CH2:21][CH2:22]Br)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][N:3]1[C:2]([I:1])=[C:6]([I:7])[N:5]=[C:4]1[CH:8]([CH3:10])[CH3:9])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)c1nc(I)c(I)[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a yellow solution of 4,5-diiodo-2-isopropyl-1H-imidazole (10.000 g; 27.629 mmol) in anhydrous DMF (140 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (1.326 g; 33.154 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (6.810 g; 30.391 mmol) in anhydrous DMF (100 ml) was added dropwise, over 1 h, with an addition funnel. After completion of the addition, the resulting mixture was further heated at 100° C. for 1 h30. The reaction mixture was cooled to 0° C., and water (300 ml) was added slowly. This mixture was extracted with ether (5×150 ml). The combined organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give an orange oil. The crude was purified by FC (DCM/MeOH=30/1) to give the pure product [2-(4,5-diiodo-2-isopropyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was further dried under HV (9.720 g; 70%). LC-MS: tR=0.82 min.; [M+H]+=506.32 g/mol.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:3].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:11][C:7]1[CH:6]=[C:5]([N:4]([C:2](=[O:3])[CH3:1])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1cccc(F)c1
Reactant: Brc1ccccc1
Product: CC(=O)N(c1ccccc1)c1cccc(F)c1
Yield: 21.2 %

Procedure:
Using 3-fluoroacetanilide (4.6 g) and bromobenzene (9.4 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:2) produced 3-fluoro-N-phenylacetanilide (1.46 g; yield, 21%) as a purple oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]#[C:10][C:11]2[C:12]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>C(Cl)Cl>[CH:20]1([NH:19][C:12]2[C:11]([C:10]#[C:9][CH2:8][O:7][C:6]3[CH:26]=[CH:27][C:3]([CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:4][CH:5]=3)=[CH:16][N:15]=[C:14]([C:17]#[N:18])[N:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#Cc1ncc(C#CCOc2ccc(CCl)cc2)c(NC2CCCCC2)n1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc(OCC#Cc3cnc(C#N)nc3NC3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
5-[3-(4-Chloromethyl-phenoxy)-prop-1-ynyl]4-cyclohexylamino-pyrimidine-2-carbonitrile (0.050 mmol) is dissolved in CH2Cl2 (2 ml) and 1-methyl-piperazine (0.10 mmol) is added at room temperature and the mixture is stirred at room temperature for overnight. Water is added and the organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 40% yield.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([Sn](C)(C)C)=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].Cl[C:17]1[N:26]=[C:25]([NH:27][CH2:28][C@H:29]2[O:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)[C:24]2[C:19](=[N:20][CH:21]=[CH:22][N:23]=2)[CH:18]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][C:9]([C:17]2[N:26]=[C:25]([NH:27][CH2:28][C@H:29]3[O:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[C:24]3[C:19](=[N:20][CH:21]=[CH:22][N:23]=3)[CH:18]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Reactant: CN(CCO)c1ccc([Sn](C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(CCO)c1ccc(-c2cc3nccnc3c(NC[C@@H]3CN(C(=O)OC(C)(C)C)CCO3)n2)cc1

Procedure:
2-(methyl(4-(trimethylstannyl)phenyl)amino)ethanol (223 mg, 0.713 mmol), (R)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (246 mg, 0.648 mmol), tetrakis(triphenylphosphine)palladium (150 mg, 0.13 mmol) was mixed in toluene, reacted at 100° C. overnight. Then it was filtrated and concentrated, purified by flash chromatography (PE: EA=2:1 to 1:1) to give crude product as a reddish-brown oil. And it was used without further purification.