Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:51].C(NCC)C.[CH3:57][O:58][CH2:59][CH2:60][NH:61][CH2:62][CH2:63][O:64][CH3:65]>CN(C=O)C.O>[ClH:51].[CH3:57][O:58][CH2:59][CH2:60][N:61]([CH2:62][CH2:63][O:64][CH3:65])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[CH:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: COCCNCCOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: O
Product: COCCN(CCOC)C(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and diethyl amine (0.16 ml, 1.17 mmol) were added and stirred for 5 min, Bis(2-methoxyethyl)amine (0.104 g, 0.786 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the amide as a yellow solid (0.04 g). The amide was dissolved in THF (2 ml), ether saturated with HCl (2 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as a yellow solid (0.035 g, 17%). M.P.: 126-129° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.07 (m, 1H), 8.74 (m, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.29 (d, J=8.3 Hz, 2H), 8.19 (m, 3H), 8.02 (m, 1H), 7.78 (m, 1H), 7.53 (d, J=8.2 Hz, 2H), 6.27 (s, 2H), 3.64 (bs, 2H), 3.58 (br.s, 2H), 3.41 (br.s, 4H), 3.30 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([O-])=O>C(O)C.C(OCC)(=O)C>[CH2:16]([S:15][C:12]1[CH:11]=[CH:10][C:9]([NH2:6])=[CH:14][CH:13]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(SCc2ccccc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(SCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Tin (II) chloride dihydrate (444 mg) was added to a stirred solution of benzyl 4-nitrophenyl sulfide (A, 704 mg) in ethanol (20 mL). The mixture was stirred at 70° C. for 2 hr under nitrogen, allowed to cool down and then poured into ice. The pH was made slightly basic (pH 7-8). The mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (565 mg) as a brown oil: 1H NMR (400 MHz, CDCl3) δ 3.59 (br s, 2H), 3.93 (s, 2H), 6.54-6.57 (m, 2H), and 7.11-7.26 (m, 7H).
Reaction SMILES: C([O:4][C@@:5]1([CH2:38][CH3:39])[C:35]2[CH:34]=[C:33]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]([N:26]([CH3:28])[CH3:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:36])[C:9]=2[CH2:8][O:7][C:6]1=[O:37])(=O)C.NN.[ClH:42]>CO.O1CCOCC1>[ClH:42].[CH3:28][N:26]([CH3:27])[C:20]1[N:19]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:18]2=[C:13]3[CH2:12][N:11]4[C:33](=[CH:34][C:35]5[C@:5]([CH2:38][CH3:39])([OH:4])[C:6](=[O:37])[O:7][CH2:8][C:9]=5[C:10]4=[O:36])[C:14]3=[N:15][C:16]3[C:17]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[N:21]=1
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CC(C)C)C(N(C)C)=N3
Agent: Cl
Agent: NN
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CC(C)C)C(N(C)C)=N3
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of (9S)-9-acetoxy-2-(dimethylamino)-9-ethyl-1-(2-methylpropyl)-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (8.7 mg, 0.023 mmol) in methanol (2 ml) and 1,4-dioxane(2 ml) cooled in an ice-bath was added anhydrous hydrazine (100 μl). The mixture was warmed to room temperature and stirred for 3 hr. 10% HCl in methanol was added dropwise to acidify the reaction mixture and the mixture was stirred at room temperature for 2 h. After concentrated under reduced pressure, the obtaining residue was purified by reversed phase column chromatography (water/methanol=1/0−1/2) to give the product (7.4 mg, 85%) as a yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1.[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]([NH2:49])[N:44]=2)=[CH:33][CH:32]=1>C(Cl)Cl>[NH2:49][C:45]1[N:44]=[C:43]([CH2:42][O:41][C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]([NH:30][C:23]([NH:10][C:8]3[N:7]([C:11]4[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:24])=[CH:32][CH:33]=2)[CH:48]=[CH:47][N:46]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: Nc1nccc(COc2ccc(N)c3ccccc23)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)n3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
A solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4) (WO 2000043384) (0.98 g, 4.26 mmol) in DCM (4.0 mL) was added dropwise over 1 hr, to a suspension of CDI (0.69 g, 4.26 mmol) in DCM (3.0 mL) and the solution was stirred at RT for 2 hr. This solution was added dropwise to a solution of 4-((4-aminonaphthalen-1-yloxy)methyl)pyrimidin-2-amine (33) (0.9 g, 2.366 mmol) in DCM (10 mL). After each 1.0 mL aliquot was added, the reaction was allowed to stir for 1 hr, and the mixture monitored by LC-MS to ensure consumption of the CDI activated 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine, without over acylation. The reaction was quenched with MeOH (20 mL), silica added (20 g) and the volatiles evaporated. The residue was subjected to column chromatography (100 g) eluting with 50 to 100% EtOAc in iso-hexane. The combined fractions were triturated from DCM (20 mL) and the solid collected, and washed with diethyl ether (50 mL) to give 1-(4-((2-aminopyrimidin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate H) as a purple solid (0.48 g, 38%): m/z 523 (M+H)+ (ES+).
Reaction SMILES: C([Cl:4])(=O)C.[OH:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([O:27][CH3:28])[C:19]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7]1=[O:29]>C(O)C>[ClH:4].[OH:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([O:27][CH3:28])[C:19]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7]1=[O:29]
Reactant: CC(=O)Cl
Agent: COc1cc2c3c(cccc3c1N1CCN(C)CC1)C(=O)N(O)C2=O
Solvent: CCO
Product: Cl
Reaction time: 0.5 h

Procedure:
2-Benzyloxy-6-bromo-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.5 g, from Example Z) was reacted with N-methylpiperazine (30 mL) following the procedure of Example 18 to give 0.5 g of 2-benzyloxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-5-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.3 g) at 40 psi in the presence of Pd/C (10%) in DMA (20 mL) afforded 0.2 g of the title compound as the free base. A solution of acetyl chloride (0.03 mL) in ethanol (1mL) was added to a solution of 2-hydroxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.12 g, 0.4 mmol) in ethanol (5 mL). The solution was stirred for 30 minutes, and the precipitate was filtered, washed with ether, and dried to give 0.13 g of the title compound as the HCl salt, mp 296-300° C.;
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)(=[O:33])=[O:32].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1>[CH3:40][C:37]1[CH:38]=[CH:39][C:34]([S:31]([N:30]([CH3:29])[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:33])=[O:32])=[CH:35][CH:36]=1.[CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC(C)O
Solvent: C1CCOC1
Product: CCCCCCC(C)N(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 21 h

Procedure:
After (racemic)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (727 mg, 2.76 mmol), N-methyl-p-toluenesulfonamide (514 mg, 2.76 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 21 hours. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give 4,N-dimethyl-N-(1-methylheptyl)benzenesulfonamide as a white solid substance (223 mg, yield: 33%/(racemic)-2-octanol).
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3][OH:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:4][CH2:3][C:2]([F:1])([F:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)(F)c1ccccn1
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)c2ccccn2)cc1

Procedure:
reacting 2,2-difluoro-2-pyridin-2-ylethanol with 4-toluenesulfonyl chloride to form 2,2-difluoro-2-pyridin-2-ylethyl 4-methylbenzenesulfonate, which is converted to compound of formula (K2); and
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13](O)=[O:14])=[C:10]([F:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[C:11]([CH2:12][C:13]([Cl:20])=[O:14])=[C:10]([F:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1c(F)cc2ncccc2c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1c(F)cc2ncccc2c1F
Temperature: 0 °C

Procedure:
(5,7-Difluoro-quinolin-6-yl)-acetic acid (1 g, 4.48 mmol) was added to an oven-dried round-bottom flask and suspended in dichloromethane (18 ml) The suspension was maintained under nitrogen atmosphere and cooled to 0° C. Next, the oxalyl chloride (470 uL, 5.38 mmol) was added slowly, followed by a catalytic amount of dimethylformamide. The solution was allowed to warm to room temperature over 2 hours. The solution was then concentrated in vacuo and dried via azeotropic distillation with toluene to afford the title compound. ES-MS m/z: 238 (M+H+) of methyl ester.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:54]([NH:56][CH2:57][CH3:58])[CH3:55]>C(#N)C>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]([N:56]([CH2:57][CH3:58])[CH2:54][CH3:55])=[O:20])[CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCNCC
Reactant: O=C(O)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CCN(CC)C(=O)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1

Procedure:
[6-(Biphenyl-4-sulfonylamino)-pyridin-2-yl]-acetic acid (0.35 g) in acetonitrile (5 mL) was treated at RT with N,N-ethyldiisopropylamine (0.16 mL), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 0.252 g) then diethylamine (0.05 mL), and the mixture was stirred at RT for 16 h. It was then partitioned between cold diluted aqueous HCl and AcOEt, the layers were separated, the organic layer dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/EtOAc 1:1) to give 2-[6-(biphenyl-4-sulfonylamino)-pyridin-2-yl]-N,N-diethyl-acetamide as a yellow solid (0.168 g). MS (ESI−): 422.2 ([M−H]−).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[C:10](=O)([O-])O.[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>C(#N)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[C:7]([O:9][CH3:10])=[O:8])=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=C(O)C1CCCCN1
Reactant: O=C([O-])O
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C1CCCCN1C(=O)Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Yield: 32 %

Procedure:
5.00 g of piperidine-2-carboxylic acid was dissolved into an aqueous 80 ml solution of saturated sodium hydrogen carbonate and stirred at a room temperature. 20 ml of an acetonitrile solution of 9.2 g of 3,4-dimethoxyphenyl acetyl chloride was dropped and stirred for 30 min. After washing the aqueous layer with ethyl acetate, the aqueous layer was adjusted to about pH 2 with concentrated hydrochloric acid and extracted with chloroform. Chloroform was distilled off and the resultant residue was refluxed for 6 hours with addition of 150 ml of methanol and 0.5 ml of concentrated sulfuric acid. After distilling off methanol, an aqueous diluted solution of sodium hydrogen carbonate was added and extracted with ethyl acetate. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified on silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to obtain 3.94 g of the above-captioned compound as yellow oil (yield: 32%).
Reaction SMILES: [N+](O[Bi])([O-])=O.[N+](O[Bi])([O-])=O.[N+](O[Bi])([O-])=O.[N+](O[Bi])([O-])=O.O.O.O.O.O.O.O.O.O[Bi:30]=O.[C:32]([OH:37])(=[O:36])[CH:33]([CH3:35])[OH:34].[N+]([O-])([O-])=O>OCC(CO)O>[C:32]([O-:37])(=[O:36])[CH:33]([CH3:35])[OH:34].[Bi+3:30].[C:32]([O-:37])(=[O:36])[CH:33]([CH3:35])[OH:34].[C:32]([O-:37])(=[O:36])[CH:33]([CH3:35])[OH:34]
Reactant: CC(O)C(=O)O
Reactant: O=[Bi]O
Agent: O=[N+]([O-])O[Bi]
Agent: O=[N+]([O-])[O-]
Solvent: OCC(O)CO
Solvent: O
Product: CC(O)C(=O)[O-]
Product: [Bi+3]
Temperature: 70 °C

Procedure:
The bismuth sub nitrate, glycerin and lactic acid were placed in a kettle and heated at 70° C. until clear. During heating, the lactic acid displaced the nitrate to form bismuth lactate;
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu]([C:11]#[N:12])C#N.[ClH:13]>O>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:11]#[N:12])=[C:1]([CH3:7])[CH:2]=1
Reactant: Cc1ccccc1
Reactant: Cl
Reactant: N#C[Cu]C#N
Solvent: O
Product: Cc1cc(Cl)ccc1C#N
Temperature: 25 °C

Procedure:
Toluene (30 mL) and ice was added to the above copper cyanide solution and then the reaction mixture was stirred vigorously. The above diazonium salt solution was then slowly added to the reaction mixture. After the addition was complete, the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then allowed to warm to room temperature (25° C.), and then stirred for another hour. The reaction mixture was then heated to 50° C. for 2 hours without stirring. The toluene phase and precipitate were then separated from the aqueous phase. To the toluene phase was added 10 mL concentrated HCl, 40 mL hot H2O, and FeCl3.6H2O (32 g, 0.118 mol) and this reaction mixture was then stirred overnight. The reaction mixture was then added to 200 mL H2O. The organic phase was then extracted with toluene, dried and evaporated under reduced pressure to produce 4-chloro-2-methylbenzonitrile as a dark brown oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH2:26][OH:27])[CH:25]=1>>[F:28][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:25][C:24]=1[CH2:26][OH:27]
Reactant: Nc1ccc(F)c(CO)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(CO)c1
Yield: 62.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 525 mg of (5-amino-2-fluorophenyl)methanol in place of the 2,4-difluoroaniline. 218 mg of N-[4-fluoro-3-(hydroxymethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:23][CH:24]1[CH:32]=[CH:31][CH2:30][CH:29]2[CH:25]1[CH2:26][NH:27][CH2:28]2.C1N2CCN(CC2)C1.O>C(#N)C.CN(C)C=O>[NH2:23][CH:24]1[CH:32]=[CH:31][CH2:30][CH:29]2[CH:25]1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH:17]=[CH2:18])[C:10]=1[F:16])[CH2:28]2
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: NC1C=CCC2CNCC12
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(F)c(N2CC3CC=CC(N)C3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 77.8 %

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.62 g of 4-amino-1,3,3a,4,7,7a-hexahydro-isoindole and 0.34 g of DABCO are refluxed for 1 hour in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. The reaction mixture is treated with 20 ml of water, and the product is filtered off with suction, washed with water and dried. 1 g of 7-(4-amino-1,3,3a,4,7,7a-hexahydro-isoindol-2-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[CH2:10]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[Cl-].[NH4+].[N-:28]=[N+]=[N-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[CH2:10][NH2:28])=[O:6])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOC(=O)NCC(COS(C)(=O)=O)C(C)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)NCC(CN)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 7 h
Yield: 202.8 %

Procedure:
To a solution of 7.00 g of 2-(N-allyloxycarbonylaminomethyl)-3-t-butyldimethylsilyloxy-1-methanesulfonyloxybutane and 1.42 g of ammonium chloride in 70 ml of N,N-dimethylformamide was added 1.73 g of sodium azide at 0° C. The mixture was stirred at 50° C. for 7 hours. After the starting material disappeared, 350 ml of ethyl acetate and 350 ml of water were added to the reaction mixture. The organic layer was washed in turn with water three times and brine. The half amount of solvent was evaporated and then 5.11 g of triphenylphosphine was added thereto portionwise. After stirring overnight, 2.15 g of 28% aqueous ammonia was added and the mixture was stirred for 8 hours, and then evaporated under reduced pressure to give 11.36 g of crude 2-(N-allyloxycarbonylaminomethyl)-3-(t-butyldimethylsilyloxy)butylamine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:33](Cl)(Cl)=[O:34].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44]>C1(C)C=CC=CC=1>[OH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:37][C:33]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:34]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)Cl
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)Nc2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a solution of COMPOUND 249 (0.1537 g, 0.50 mmol) in toluene (5 mL) was added DIPEA (0.17 mL, 1.00 mmol), and at 0° C. was added a 20% phosgene solution in toluene (0.27 mL, 0.59 mmol). The reaction was stirred at room temperature for 2 hours, then concentrated. The remaining solid was dissolved in DMF (5 mL), and DIPEA (0.17 mL, 1.00 mmol) and 2-aminophenol (0.2353 g, 2.50 mmol) were added, and stirred at room temperature for 20 hours. The mixture was concentrated, and saturated NaHCO3 (20 mL) was added and extracted with CH2Cl2 (3×40 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 then 20:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography (20:1:1 CH2Cl2-MeOH—NH4OH) provided 56.0 mg (24%) of COMPOUND 343 as a brown solid. 1H NMR (CD3OD) δ 1.70-1.78 (m, 2H), 1.91-1.95 (m, 2H), 2.15 (s, 6H), 2.68 (t, 3H, J=12.6 Hz), 3.85 (s, 4H), 4.23 (d, 2H, J=14.1 Hz), 6.68-6.71 (m, 2H), 7.08-7.11 (m, 2H), 7.21-7.25 (m, 2H), 7.55 (d, 2H, J=7.8 Hz), 8.27 (d, 2H, J=4.5 Hz). 13C NMR (DMSO) δ 17.76, 27.09, 44.12, 54.56, 57.81, 115.03, 122.36, 122.84, 128.41, 132.36, 133.23, 138.16, 145.97, 152.75, 155.37, 157.39. ES-MS m/z 446.5 (M+H). Anal. Calcd. for C26H31N5O2.0.3(CH2Cl2).0.2H2O: C, 67.06; H, 6.76; N, 14.87. Found: C, 67.17; H, 6.83; N, 14.58.
Reaction SMILES: [CH2:1]([N:3]([CH3:7])[C:4]([NH2:6])=[S:5])[CH3:2].C[I:9].[C:10](OCC)(=O)C>CN(C)C=O>[IH:9].[CH2:1]([N:3]([CH3:7])[C:4](=[NH:6])[S:5][CH3:10])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CI
Reactant: CCN(C)C(N)=S
Solvent: CN(C)C=O
Product: CCN(C)C(=N)SC
Product: I
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5.8 g (49 mmol) of N-ethyl-N-methylthiourea was dissolved in 10 ml of N,N-dimethylformamide. 8.8 g (62 mmol) of methyl iodide was added at room temperature, and the mixture was stirred at room temperature for 15 hours. 500 ml of ethyl acetate was added to the mixture, and precipitated crystals were collected by filtration and then washed with ethyl acetate to obtain 3.1 g of N-ethyl-N-methyl-S-methylisothiourea hydroiodide as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:4]=2[O:5][C:6]=1[CH3:7].C(O)(=O)C>C(O)C.O1CCOCC1.[Fe]>[NH2:12][C:8]1[C:4]2[O:5][C:6]([CH3:7])=[C:2]([Br:1])[C:3]=2[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1Br
Agent: [Fe]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1oc2c(N)cccc2c1Br
Yield: 98.9 %

Procedure:
To a solution of 3-bromo-2-methyl-7-nitrobenzo[b]furan (300 mg) and acetic acid (776 mg) in a mixture of ethanol (6 ml) and dioxane (1.5 ml) was added iron (722 mg) at 50° C. The mixture was refluxed for 1.5 hours and the insoluble material was filtered off. The filtratate was evaporated in vacuo with toluene. The residue was extracted with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and it was extracted with ethyl acetate from aqueous layer. The organic layer was combined and washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, and evaporated in vacuo to give 7-amino-3-bromo-2-methylbenzo[b]furan (262 mg) as a white solid.