Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=4)[CH2:17][CH2:16][N:15]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CCCCCC.CN(C)C=O>[C:31]([O:30][C:29](=[O:35])[NH:28][CH2:27][CH2:26][O:24][C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][N:15]=[C:14]2[C:10]2([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:19][CH:20]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2

Procedure:
Sodium hydride (0.626 g, 15.64 mmol, 60% suspension in mineral oil) was washed under dry conditions under nitrogen atmosphere with n-hexane. Dimethylformamide (20 mL) was added followed by 1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (2.1 g, 7.11 mmol) under stirring. After the exothermic reaction had ceased stirring was continued at room temperature for 1 h before tert-butyl (2-bromoethyl)carbamate (4.78 g, 21.33 mmol) was added dropwise as a solution in dimethylformamide (10 mL). The reaction mixture was stirred at room temperature over night. The solvent was evaporated in vacuo. Ice water was added (60 mL) and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane:methanol=100:1). Yield: 2.5 g (5.7 mmol, 36%).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([C:31]1[CH:32]=[C:33]([C:42]2[N:43]=[C:44]([CH:47]=O)[S:45][CH:46]=2)[CH:34]=[C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:36]=1[OH:37])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(OC(=O)C)(=O)C>[C:27]([C:31]1[CH:32]=[C:33]([C:42]2[N:43]=[C:44]([CH:47]=[C:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])[S:45][CH:46]=2)[CH:34]=[C:35]([C:38]([CH3:39])([CH3:40])[CH3:41])[C:36]=1[OH:37])([CH3:28])([CH3:29])[CH3:30]
Reactant: O=C1NCCC1Br
Reactant: CC(C)(C)c1cc(-c2csc(C=O)n2)cc(C(C)(C)C)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2csc(C=C3CCNC3=O)n2)cc(C(C)(C)C)c1O
Temperature: 70 °C

Procedure:
16.0 g (91 mmol) of 3-bromopyrrolidin-2-one were heated to boiling in 30 ml of acetic anhydride for 1 hour. After evaporating the reaction mixture t dryness under reduced pressure, the residue was dissolved in 50 ml of tetrahydrofuran and, after adding 26.2 g (0.1 mol) of triphenylphosphine, heated under reflux for 5 hours. It was then concentrated again, the residue was dissolved in 300 ml of ethanol and 24.7 g (78 mmol) of the aldehyde from Example 2 b1) and 27 ml (0.36 mol) of triethylamine were added. After heating the mixture at 70° C. for 2 hours, the yellow precipitate was filtered off and washed with ethanol. The crystal magma is dissolved in about 2 1 of chloroform, the solution is washed several times with saturated sodium chloride solution and dried over Na2SO4, and the chloroform phase is concentrated to a third. Yellow crystals deposit on allowing to stand for a relatively long time.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[NH:18])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCC(=O)CC>[ClH:3].[CH2:8]([C:7]1([CH2:12][CH3:11])[N:15]=[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:18]1)[CH3:9]
Reactant: CCCCCCCNC(=N)NC(=N)NCc1ccccc1
Agent: Cl
Solvent: CCC(=O)CC
Solvent: CO
Product: CCCCCCCNC1=NC(CC)(CC)N=C(NCc2ccccc2)N1

Procedure:
100 ml of methanol, 150 ml of 3-pentanone, and 0.5 ml of concentrated hydrochloric acid were added to 6.0 g (15.6 mmol) of N1-benzyl-N5-heptyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of methanol, and to the solution were added 80 ml of water and 5 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water, and acidified with 6N hydrochloric acid, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1)) to obtain 4.7 g of a pale yellow resinous solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[N:22][CH:23]=[C:18]([S:17][CH3:16])[CH:19]=2)[C:11]=1[CH3:12]
Reactant: CSc1cncc(B(O)O)c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (600 mg, 2.419 mmol), 5-(methylthio)pyridin-3-ylboronic acid (429 mg, 2.54 mmol), PdCl2(PPh3)2 (170 mg, 0.242 mmol), sodium carbonate (769 mg, 7.26 mmol), 1,4-dioxane (6.5 mL), and water (1.6 mL) at 95° C. for 2 h. Purification by column chromatography (silica gel, 0-30% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylthio)pyridin-3-yl)quinoline. Mass Spectrum (ESI) m/e=337.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][N:17](C(OC(C)(C)C)=O)[CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:8][C:7]=2[CH:37]=1)#[N:2].N1CCCC1.[ClH:43].Cl.Cl.N1C=C(CN2C3C=CC([C:63]4[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1>>[ClH:43].[ClH:43].[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH2:36][CH2:64][N:65]3[CH2:63][CH2:68][CH2:67][CH2:66]3)(=[O:34])=[O:35])[CH2:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Agent: Cl
Solvent: C1CCNC1
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)CCN1CCCC1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Yield: 46 %

Procedure:
Example 327 was prepared in 46% yield as a light yellow solid from Compound A of Example 250 and pyrrolidine as described for Compound B of Example 250. MS (M+H)+ =505.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Product: Cc1ccc2nc(Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Methyl-1,3-dihydro-2H-benzimidazol-2-one (13.1 g, 88.5 mmol) and phosphorus oxychloride (130 ml, freshly distillated) was charged into three-neck round-bottom flask. The mixture was heated up to boiling point till homogeneous solution was formed. After that the dried hydrogen chloride was bubbled through inlet gas-pipe into the reaction mixture. The mixture was boiled for 15 hours. Excess of phosphorus oxychloride was distillated in vacuo. Mixture of ice and water (250 ml) was added to residue. The obtained suspension was cooled to the room temperature and filtered. Filtrate was alkalinized by aqueous ammonia solution till pH 8, cooled by cold water and filtered crude 2-chloro-6-methyl-1H-benzimidazole. White powder was crystallized from aqueous methanol (water-methanol: 1:1, 200 ml), washed by aqueous methanol and dried in a desiccator under phosphorous oxide in vacuo. Yield: 8.17 g (55%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[N:8]=[C:7]([Cl:13])[N:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[CH:3]=2)[N:8]=1
Reactant: Clc1ncc2cc(Br)cc(Cl)c2n1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2cc(Cl)c3nc(Cl)ncc3c2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
A mixture of 6-bromo-2,8-dichloroquinazoline (4.0 g, 14.5 mmol), 3,5-dimethoxyphenylboronic acid (4.23 g, 16.0 mmol), cesium carbonate (9.42 g, 29.0 mmol) and Pd(PPh3)2Cl2 (220 mg, 0.70 mmol) in THF (200 mL) and water (10 mL) was degassed with nitrogen three times, and stirred at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, directly concentrated and purified by silica gel chromatography (petroleum ether: dichloromethane=2:1˜1:1) to get the title compound as a yellow solid (2.0 g, 41%). MS (ES+) C16H12Cl2N2O2 requires: 334, 336, found: 335, 337 [M+H]+.
Reaction SMILES: CS(C)=O.Cl.Cl.[NH2:7][CH:8]1[CH2:11][NH:10][CH2:9]1.[NH2:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[N:16]=[C:15]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:33])=[C:28](F)[C:29]=3[Cl:31])[C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22]2)[C:14]=1[F:38]>C(N(CC)CC)C>[NH2:7][CH:8]1[CH2:11][N:10]([C:28]2[C:29]([Cl:31])=[C:30]3[C:25]([C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22][N:21]3[C:15]3[C:14]([F:38])=[C:13]([NH2:12])[C:18]([F:19])=[C:17]([F:20])[N:16]=3)=[CH:26][C:27]=2[F:33])[CH2:9]1
Reactant: Nc1c(F)c(F)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Reactant: NC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(F)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c1F
Yield: 50.2 %

Procedure:
To 1 ml dimethylsulfoxide solution of 70 mg of 3-aminoazetidine dihydrochloride and 250 mg of triethylamine at 80° C. was added 150 mg of 1-(4-amino-3,5,6-trifluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was allowed to cool and decanted with diethylether. Ethanol was added to the residue to disperse the solid content, and the solid content was collected by filtration, washed with ethanol, and dried to obtain 85 mg of the title compound as a pale yellow powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:5](=[N:15][N:16]([CH3:18])[N:17]=2)[NH:6][C:7]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:8]=2[N:9]=1.CS(C)=O.[CH3:23][N:24]1[CH2:29][CH2:28]N[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[NH:6][C:5]3=[N:15][N:16]([CH3:18])[N:17]=[C:4]3[C:3]([N:2]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[N:9][C:8]=2[CH:10]=1
Reactant: Cn1nc2c(n1)C(N)=Nc1cc(F)ccc1N2
Reactant: CN1CCNCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CCN(C2=Nc3cc(F)ccc3Nc3nn(C)nc32)CC1
Temperature: 125 °C

Procedure:
10-Amino-7-fluoro-2-methyl-2,4-dihydro-1,2,3-triazolo[4,5-b][1,5]benzodiazepine hydrochloride (2.68 g) was added to a mixture of dry dimethyl sulphoxide (10 ml), toluene (10 ml) and dry N-methyl piperazine (3.3 ml), which had been degassed with nitrogen for 20 minutes. The stirred solution was then heated at 125° C. (oil-bath) under nitrogen for five hours, cooled to room temperature, and distilled water (33.3 ml) added, keeping the temperature below 25° C. After stirring at 5° C. for half an hour, the suspension obtained was filtered off and dried at 70° C. under reduced pressure to leave a yellow crystalline solid, which was recrystallised from ethyl acetate/n hexane, melting point 195°-197° C.