Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>O.CCO>[OH:14][NH:13][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[NH:2]
Reactant: NO
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc2[nH]ccc2c1
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
A mixture of the product of Step A (0.2 g; 1.41 mmol), HCl×H2NOH (0.36 g; 5.2 mmol), and Na2CO3 (0.26 g; 2.44 mmol) in H2O (8 ml) and EtOH (2 ml) was gently stirred for 10 min, then refluxed overnight under N2. After cooling most of the ethanol was removed under reduced pressure and the product was extracted with EtOAc (20 ml). The organic phase was separated, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.23 g; 92%), as a creamy foam. 1H-NMR (CDCl3+CD3OD) 1.71 (broad s, H2O); 4.93* (broad s, 0.5H); 6.55 (d, 1H, J=3 Hz); 7.21 (d, 1H, J=3 Hz); 7.28-7.42 (m, 2H); 7.87 (d, 1H, J=1 Hz); 8.63* (broad s, 0.3H).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])=[N:2]1.ClC1C=CN=CC=1CC1C=CC=CC=1C(OCC)OCC>>[O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])=[N:2]1
Reactant: O=Cc1ccccc1-c1noc2ccncc12
Agent: CCOC(OCC)c1ccccc1Cc1cnccc1Cl
Product: O=Cc1ccccc1-c1noc2ncccc12

Procedure:
2-(Isoxazolo[4,5-c]pyridin-3-yl)-benzaldehyde starting from (4-chloropyridin-3-yl)-2-(diethoxymethyl)-phenylmethane; 1H-NMR (200 MHz, CDCl3) d 10.26 (CHO).
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7](Cl)[CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([CH3:3])[CH3:2].[C:15]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC(C)C1Cc2cccc(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: CC(C)C1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Temperature: 80 °C
Yield: 97.3 %

Procedure:
28.0 g of 2-isopropyl-7-chloro-1-indanone, 28.64 g of 4-tert-butylphenylboronic acid, 35.56 g of sodium carbonate, 302 ml of ethylene glycol and 21.6 ml of water are placed in a reaction vessel. The mixture is degassed a number of times by careful application of an oil pump vacuum and subsequent admission of argon, and thus saturated with argon. It is heated to 80° C. and a freshly prepared catalyst solution comprising 60.23 mg of palladium acetate and 1.79 ml of an aqueous TPPTS solution (0.6 molar) in 25 ml of water is then added while stirring vigorously and the reaction mixture is refluxed for 5 hours with further stirring until completely reacted. After cooling to room temperature, 300 ml of water are added. After renewed cooling to room temperature, the ethylene glycol phase is washed 6 times with a total of 900 ml of toluene. The combined toluene phases are washed twice with a total of 250 ml of sodium chloride solution and dried over 150 g of sodium sulfate. Removal of the solvent on a rotary evaporator, drying of the residue and subsequent distillation in an oil pump vacuum gives 40 g (97%) of 2-isopropyl-7-(4′-tert-butylphenyl)-1-indanone as an orange-brown, viscous oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1.CCN(C(C)C)C(C)C>CCO>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[N:20][CH:19]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Yield: 88.6 %

Procedure:
A mixture of (R)-tert-butyl pyrrolidin-3-ylcarbamate (250 mg, 1.34 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (206 mg, 1.34 mmol) and DIPEA (0.35 mL, 2.01 mmol) in EtOH (3 mL) was stirred at reflux temperature for 16 hours. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (15 mL), and filtered. The filtrate was washed with brine (3×5 mL), dried over anhydrous Na2SO4, and concentrated to give the title compound (360 mg, 88% yield). MS (m/z): 304 (M+H)+.
Reaction SMILES: FCCC[O:5][C:6]([C:8]1[C:13]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:12][C:11]([O:29][CH2:30][CH2:31][CH2:32][F:33])=[CH:10][N:9]=1)=[O:7].COC(C1C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC(OCCCF)=CN=1)=O.[Li+:64].[OH-].[ClH:66]>C1COCC1.C1(C)C=CC=CC=1>[C:25]([O:24][C:22]([N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=[C:11]([O:29][CH2:30][CH2:31][CH2:32][F:33])[N:12]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26].[Cl-:66].[Li+:64]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(OCCCF)cnc1C(=O)OCCCF
Reactant: Cl
Agent: COC(=O)c1ncc(OCCCF)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(OCCCF)cnc1C(=O)O
Product: [Cl-]
Reaction time: 5.5 h

Procedure:
To a solution of 3-(di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylic acid 3-fluoro-propyl ester and 3-(di-tert-butoxycarbonyl-amino)-5-(3-fluoro-propoxy)-pyrazine-2-carboxylic acid methyl ester (395 mg, 0.92 mmol) in THF (10 ml) was added 0.5N LiOH (2.02 ml, 1.01 mmol) and the mixture was stirred for 5.5 h. To the reaction mixture was added 1N HCl (0.92 ml, 0.92 mmol) after stirring for 5 min toluene was added and the solvents were evaporated to provide the title compound together with lithium chloride as a light yellow solid. The mixture was used for coupling reactions without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1F
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(I)cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of 4-iodophenol (25.0 g), 2-fluorobenzaldehyde (14.14 g), potassium carbonate (31.5 g) and dimethylformamide (500 ml) was heated at 120° C. under nitrogen with stirring for 15 hours. The mixture was cooled to ambient temperature and filtered. Water (500 ml) was added to the filtrate and the mixture was extracted with ethyl acetate to give a solid which was triturated with hot hexane (500 ml). The supernatant liquid was decanted from a residual gum and cooled. The solid which precipitated was collected by filtration to give 2-(4-iodophenoxy) benzaldehyde, m.p. 84.5-86° C.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([O:25][CH3:26])(=[O:24])[C:22]#[CH:23]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:6]2[N:7]1[CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: C#CC(=O)OC
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
(ba) A suspension of 31.65 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) in 770 ml of toluene was treated with 10.94 g of methyl propiolate, the mixture was heated under reflux until the reaction has finished, the reaction mixture was evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). There was obtained methyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate as yellow crystals of m.p. 116° (from ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C(C)C)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)C(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 2-(4-isobutyrylbenzyl)-3-oxopentanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:47][CH2:48][CH2:49][CH3:50])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCN
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cccc(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and propylamine (8.2 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (15 mg, 53%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:10]([C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:9](=[O:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.BrC1N=C2N([C@H:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])C(=O)NC2=NC=1.C(=O)([O-])[O-].[Cs+].[Cs+].COS(OC)(=O)=O.[CH3:53][N:54](C)C=O>>[CH3:20][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]4[C:34]=3[CH:32]=[CH:33][CH:53]=[N:54]4)[N:3]=[C:4]2[N:10]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:9]1=[O:19]
Reactant: CN(C)C=O
Reactant: C[C@@H](c1ccccc1)n1c(=O)n(C)c2ncc(Br)nc21
Reactant: C[C@@H](c1ccccc1)n1c(=O)[nH]c2ncc(Br)nc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COS(=O)(=O)OC
Product: C[C@@H](c1ccccc1)n1c(=O)n(C)c2ncc(-c3cccc4ncccc34)nc21
Temperature: 55 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
(S)-5-Bromo-1-methyl-3-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. To a solution of (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.300 g, 0.943 mmol) in dimethylformamide (3 mL) was added cesium carbonate (excess) followed by dimethylsulfate (0.130 g, 1.03 mmol). The solution was heated to 55° C. in a screw capped tube. After one hour, the solution was filtered to remove cesium carbonate salts. The filtrate was condensed under reduced pressure and the crude product purified via Biotage silica gel chromatography (5-50% ethyl acetate/hexanes) to afford the title compound (0.306 g, 83% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.57 (d, 2H), 7.32 (m, 3H), 5.77 (q, 1H), 3.42 (s, 3H), 2.04 (d, 3H); 13C NMR (75 MHz, CHCl3) δ 52.6 (C═O); MS (ESI) m/z 333.3 [M+1]+, 335.3 [M+2]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:36][C:37]1[S:38][C:39]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:40]=2[N:41]=1>>[N+:46]([C:44]1[CH:43]=[CH:42][C:40]2[N:41]=[C:37]([NH:36][C:13]([C:12]3[C:11]([NH:10][C:4]4[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[N:19][CH:18]=[CH:17][CH:16]=3)=[O:15])[S:38][C:39]=2[CH:45]=1)([O-:48])=[O:47]
Reactant: O=C(O)c1cccnc1Nc1cc(F)c(F)c(F)c1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)c1cccnc1Nc1cc(F)c(F)c(F)c1
Temperature: 27 °C
Reaction time: 9 h

Procedure:
Compound 13 (185 mg, 1 mmol) and 3,4,5-trifluoro aniline (19, 147 mg, 1 mmol) was taken in ethylene glycol and refluxed at 150° C. for 5 h. Then the reaction mixture was cooled and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain Ethyl 2-(3,4,5 trifluoroanilino) nicotinate (26) as pure product. Ethyl 2-(3,4,5 trifluoroanilino) nicotinate (26, 296 mg, 1 mmol) were refluxed with 2N NaOH in ethanol for 2 h. The reaction mixture was cooled and left acidified with 2N HCl white solids obtained, filtered and washed with water to give pure compound of 2-(3,4,5-trifluorophenylamino) nicotinic acid (33). To a stirred solution of 2-(3,4,5-trifluorophenylamino) nicotinic acid (33, 252 mg, 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino 6-nitro benzothiazole (37, 137 mg, 0.7 mmol) were added, then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (8) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][C:14]#[CH:15]>>[C:16]1([CH2:12][CH2:13][C:14]#[C:15][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CCCc1ccccc1
Reactant: Clc1ccc2ccccc2n1
Product: C(#Cc1ccc2ccccc2n1)CCc1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-chloroquinoline (300 mg, 1.83 mmol) and 1-(but-3-ynyl)benzene (200 mg, 1.54 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 148 mg (0.57 mmol, 37%) of 2-(4-phenylbut-1-ynyl)quinoline as an orange oil.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccccc1-c1ccc2c(c1)CCC2O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccccc1-c1ccc2c(c1)CCC2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(1-hydroxy-indan-5-yl)-benzonitrile (3.3 grams, 14 mmol) and pyridine (2.4 mL, 30 mmol)in CH2Cl2 (30 mL) at 0° C. was added thionyl chloride (3.3 grams, 2.04 mL, 28 mmol). The reaction mixture was allowed to warm slowly to room temperature. After 1 hour, the reaction mixture was cooled to 0° C., quenched with saturated aqueous NaHCO3 (10 mL) and diluted with methylene chloride (CH2Cl2) (100 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL), dried (MgSO4) and concentrated in vacuo to give a yellow oil. 1H NMR (250 MHz, CDCl3): d 7.78 (1H, d), 7.65 (1H, t), 7.48 (m, 5 H), 5.48 (dd, 1 H), 3.25 (m, 1 H), 2.98 (m, 1 H), 2.67 (m, 1 H), 2.45 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[N:17][OH:18])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1.C(N(CC)CC)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(#N)C>[NH2:1][C:2]1[N:6]([C:7](=[N:17][O:18][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(N)n(C(=NO)c2cccc([N+](=O)[O-])c2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)ON=C(c2cccc([N+](=O)[O-])c2)n2nc(C)cc2N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
7.4 g (0.028 mol) of 5-amino-1-(3-nitro-benzohydroximoyl)-3-methyl-pyrazole are treated in 90 ml of absolute acetonitrile with 4 ml (0.028 mol) of triethylamine and then, with stirring at room temperature, are treated dropwise with a solution of 5.55 g (0.029 mol) of 4-tosyl chloride in 150 ml of absolute acetonitrile. Stirring is continued for 1 hour and then the mixture is evaporated to dryness. The residue is treated with water and ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated under vacuum. The oily residue obtained in this way is crystallised from ethanol. 8.5 g (72%) of 5-amino-3-methyl-1-(O-tosyl-3-nitrobenzohydroximoyl)-pyrazole with a m. pt. of 156°-158° C. are obtained. The substance is light-sensitive. On recrystallising twice from ethanol, the m. pt. is 165°-169° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[C:28]12([NH2:38])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>C(Cl)(Cl)Cl>[C:28]12([NH:38][C:12]([C:9]3[C:8](=[O:15])[N:7]4[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]4=[N:11][CH:10]=3)=[O:14])[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC34CC5CC(CC(C5)C3)C4)c(=O)n12
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
A mixture containing 4.08 (0.02 mole) of 6-methyl-4-oxo-4H-pyrido[1.2-a]pyrimidine-3-carboxylic acid and 3.1 ml (0.022 mol) of triethylamine in 120 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 2.52 ml (0.026 mol) of methyl chloroformate in 10 ml of chloroform is dropped to the above mixture at -15° C. during 10 minutes. After stirring for 5 minutes, 3.33 g (0.022 mol) of 1-adamantanamine dissolved in 20 ml of chloroform are dropped to the above solution at -15 0° C. during 15 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 4.4 g (65.2%) of the named product as pale yellow crystals after recrystallization from ethanol, m.p.: 190°-193° C.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14](O)=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].C(OC(NC[C@@H](CCCCC)C(O)=O)=O)C1C=CC=CC=1.N1C=CC=CC=1.[F:49]C1N=C(F)N=C(F)N=1>ClCCl>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([F:49])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Agent: CCCCC[C@H](CNC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a 250 mL round-bottomed flask was added (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoic acid (WO 2003101442, also named (2R)-[(benzyloxyformylamino)methyl]heptanoic acid) (4.40 g, 15 mmol) in dichloromethane (60 mL), followed by pyridine (1.453 mL, 18.00 mmol) and 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (2.168 g, 16.05 mmol). The reaction mixture was stirred at room temperature for 2 h, then was diluted with DCM, and washed with 5% Citric acid (150 mL) and sat. NaHCO3 (150 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography to provide (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl fluoride as a colorless oil (1.88 g, 42%). LCMS: (M+H)+: 296.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[S:12]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:15][CH3:16])(=[O:14])=[O:13]>>[S:12]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O-:15])(=[O:14])=[O:13].[CH3:16][C:8]1[N:7]=[C:6]2[NH+:11]=[C:3]([S:2][CH3:1])[S:4][C:5]2=[CH:10][CH:9]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1nc2ncccc2s1
Product: CSc1[nH+]c2nc(C)ccc2s1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C

Procedure:
To 0.626 g of 2-methylthiothiazolo[4,5-b]pyridine (Smith, K, Lindsay, C., Morris, I. K, Matthews, I. and Pritchard, G. J., Sulfur Letters 17, 197-216 (1994)), is added 0.71 g methyl tosylate. The mixture is heated at 120° C. for one hour. After cooling, the resulting oily mixture is washed with 10 mL of ethyl acetate. After the ethyl acetate is decanted, Compound 5 is isolated as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][C:21]=1[F:28]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][C:21]=1[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: OCc1ccc(Br)c(F)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(CO)cc1F

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and (4-bromo-3-fluorophenyl)methanol (Intermediate 9), the title compound was obtained as a dark brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[CH:22]=[CH:23][C:24]=1[NH2:25]>>[NH2:8][C@H:12]([C:13]1[NH:25][C:24]2[CH:23]=[CH:22][C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)=[CH:20][C:19]=2[N:18]=1)[CH2:11][OH:10]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)COC1(C)C
Product: N#Cc1ccc(-c2ccc3[nH]c([C@@H](N)CO)nc3c2)cc1

Procedure:
The title compound was prepared according to Method 1 using (S)-3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidine-4-carboxylic acid and 3′,4′-diaminobiphenyl-4-carbonitrile (Preparation 82). The residue was purified through an SCX cartridge followed by reverse phase column chromatography eluting with 0-60% MeCN in water.