Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6](CO)=[CH:5][C:4]=1[CH3:11].S(Cl)([Cl:14])=O.Cl[CH2:17][Cl:18]>>[Cl:14][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:17][Cl:18])=[CH:5][C:4]=1[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)ccc1CO
Reactant: ClCCl
Product: Cc1cc(CCl)ccc1CCl
Yield: 72 %

Procedure:
A 200 ml round-bottomed flask was charged with the entire amount (2.7 g) of the above 2,5-bis(hydroxymethyl)toluene, and 60 ml of dichloromethane was added thereto and suspended therein by stirring the mixture. Added dropwise thereto was 4 ml (5.5 mmol) of thionyl chloride, and the resultant mixture was stirred at room temperature for 3 hours and subjected to extraction by adding 50 ml of water. An organic layer formed was washed with water and with salt water, and the solvent was distilled off. The residue was purified by silica gel column chromatography using 30 g of silica gel to give 2.5 g (13 mmol) of 2,5-bis(chloromethyl)toluene (yield 72%). 2.3 Grams (12 mmol) of this 2,5-bis(chloromethyl)toluene and 6.6 g,(26.4 mmol) of triphenylphosphine were added to 45 ml of DMF, and the resultant mixture was stirred under heat at 130° C. for 2 hours. After the reaction mixture was allowed to cool, a white powder formed was separated by filtering, and washed twice with 10 ml of DMF and 20 ml of ether to give 7.9 g of white crystals of 2-methylxylylenebistriphenylphosphonium chloride (yield 95%).
Reaction SMILES: [C:1]([C:4]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[C:25]([CH3:28])[CH:24]=[C:23]4[N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[C:10]=2[Cl:34])[CH:6]=[CH:7][CH:8]=1)(O)=[O:2].Cl.C([N:38]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[C:1]([C:4]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[C:25]([CH3:28])[CH:24]=[C:23]4[N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[C:10]=2[Cl:34])[CH:6]=[CH:7][CH:8]=1)(=[O:2])[NH2:38]
Reactant: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(=O)O)c3Cl)c2n1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(N)=O)c3Cl)c2n1
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
To a solution of 2-carboxy-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (80 mg) in N,N-dimethylformamide (2 ml) were added 1-ethy1-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.3 mg) and 1-hydroxybenzotriazole (30.7 mg) at ambient temperature, and the mixture was stirred for 1.5 hours at the same temperature. To the mixture was added conc. ammonia solution (12 mg) at ambient temperature, and the mixture was stirred for 2 days at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The separated organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1, V/V) to give 2-carbamoyl-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (31 mg) as amorphous powder.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH3:11])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N1([C:68]2[CH:79]=[CH:78][C:74]([N+:75]([O-:77])=[O:76])=[CH:73][C:69]=2[N+:70]([O-:72])=[O:71])CCC[C@H]1C(N[C@H](C(NCC(O)=O)=O)CCC(=O)N)=O>>[NH:1]([C:68]1[CH:79]=[CH:78][C:74]([N+:75]([O-:77])=[O:76])=[CH:73][C:69]=1[N+:70]([O-:72])=[O:71])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH3:11])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: NC(=O)CC[C@H](NC(=O)[C@@H]1CCCN1c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)NCC(=O)O
Product: CC[C@H](C)[C@H](Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
Boc-Ile-Ala-Gly-D-Arg(NO2)-OBzl (900 mg, 1.4 m mol) was demasked with respect to the N-masking group, and coupled with DNP-Pro-Gln-Gly-OH (580 mg, 1.4 m mol) in the manner similar to that of Example 1, paragraph 7).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[SH:14]>CC[O-].[Na+]>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Sc1cccs1
Agent: CC[O-]
Agent: [Na+]
Product: Clc1cnc(Sc2cccs2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
2,5-Dichloropyrimidine (11.3 mmol) was added to a solution of thiophene-2-thiol (12.3 mmol) in ethanolic (50 ml) 0.246 M NaOEt. The reaction mixture was stirred at room temperature for 15 min and heated under reflux for 2 h. The solvent was then evaporated, the residue extracted with chloroform, the chloroform solution washed with 2 M NaOH and the dried (MgSO4) solution evaporated to leave the sulfide; yield 89%, m.p. 65° C. (pet. ether b.p. 100° C.). 1 H NMR (CDCl3); δ7.03, 7.26, 7.53 (thiophene), 8.40 (H-4, H-6).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6]1.[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cn1nc(-c2ccc(OC)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccccc3)n(CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
30.8 g of (3-(4-methoxy-phenyl)-5-phenyl-(1,2,4)triazol-1-yl)-acetic acid methyl ester was dissolved in 140 mL dioxane and a solution of 0.8 g LiOH in 140 mL of water was added. The mixture was stirred for 4 h at RT. The mixture was acidified with HCl-solution and the precipitate was filtered to give 9.0 g of the desired product as mixture of isomers. These isomers were separated by HPLC chiral (method 1; solvent MeOH: DCM=1:1, concentration: 90 mg/mL). Rt: 1.26 min (method A) and 1.24 min., (M+H)+: 310
Reaction SMILES: [CH3:1][N:2]1[C@H:14]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=32)[CH2:4][CH2:3]1.[I:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CC(O)=O>[I-:15].[CH3:1][N:2]1[C@H:14]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N+:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:13]=32)[CH2:4][CH2:3]1
Reactant: CN1CC[C@H]2CCc3ccncc3[C@H]21
Reactant: CCCCCCCCI
Solvent: CC(=O)O
Product: CCCCCCCC[n+]1ccc2c(c1)[C@@H]1[C@H](CC2)CCN1C
Product: [I-]
Yield: 68.3 %

Procedure:
To a stirred solution of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinoline (100 mg, 0.53 mmol) in AcOH (2 ml) was added 1-iodooctane (383 mg, 1.59 mmol). The mixture was heated at reflux under nitrogen for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 155 mg (68%) of cis-1-methyl-8-octyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACO) as a brown oil. 1H NMR (300 MHz, CDCl3) δ9.16 (1H, s, C9-H), 9.03 (1H, d, J6.0 Hz, C7-H), 7.82 (1H, d, J6.0 Hz, C6-H), 4.86 (2H, m. pyCH2), 3.66 (1H, d, J8.4 Hz, C9b-H), 2.43 (3H, s, NCH3), 1.55-3.20 (9H, m, CH2+CH), 1.99 (2H, m, pyCH2CH2), 1.00-1.50 (10H, m, 5×CH2), 0.81 (3H, t, J6.9 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ161.8, 143.5, 142.5, 138.2, 127.6, 63.4, 61.4, 55.8, 41.2, 35.8, 32.1, 31.8, 30.0, 29.2×2, 27.8, 27.6, 26.2, 22.7, 14.2.
Reaction SMILES: [C:1]([C:5]1[C:6]([CH3:29])([CH3:28])[CH2:7][O:8][C:9]=1[C:10]1[CH:26]=[C:25]([OH:27])[C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[O:31]=[O:32]>C(Cl)Cl>[C:1]([C:5]12[O:32][O:31][C:9]1([C:10]1[CH:26]=[C:25]([OH:27])[C:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[O:16][C:12]=3[CH:11]=1)[O:8][CH2:7][C:6]2([CH3:29])[CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=O
Reactant: COc1ccc(-c2nc3c(O)cc(C4=C(C(C)(C)C)C(C)(C)CO4)cc3o2)cc1
Agent: [Na]
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(O)cc(C45OCC(C)(C)C4(C(C)(C)C)OO5)cc3o2)cc1
Yield: 93.1 %

Procedure:
To 5 mL of methylene chloride were added 1.0 mg of TPP and 95.1 mg (0.24 mmol) of 4-t-butyl-5-(4-hydroxy-2-(p-methoxyphenyl)benzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [67]), and the mixture was externally irradiated with a 940 W sodium lamp in an oxygen atmosphere for30 minutes. After the resulting mixture was concentrated, the concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=3:1), and then followed by recrystallization from the mixture of methylene chloride and hexane to obtain 95.8 mg of 5-t-butyl-1-(4-hydroxy-2-(p-methoxyphenyl)benzo[d]oxazol-6-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [68]) as colorless granular micro-crystal. Yield 93.1%.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[CH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O=P(Cl)(Cl)Cl.O.CN([CH:26]=[O:27])C>>[CH:26]([C:5]1[CH:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2](=[O:1])[N:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2)=[O:27]
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reaction time: 1 h
Yield: 93 %

Procedure:
Ethyl 4-oxo-4H-quinolizine-3-carboxylate (1) (1 g, 4.0 mmol) was dissolved in 2 ml DMF followed by the addition of POCl3 (1.0 ml, 11 mmol). The reaction mixture was stirred for 1 h, poured into 100 ml water and extracted three times with 100 ml dichloromethane. Evaporation of the organic solvent gave a sticky yellow solid, which was further purified by flash chromatography (ethyl acetate), followed by overnight stirring with 10 ml ether to remove the last traces of DMF. Filtration of the suspension and drying in vacuo gave a bright yellow powder (920 mg, 93%). M.p. 179-181° C. 1H NMR (δ, CDCl3): 1.43 (t, J=7 Hz), 4.42 (q, J=7 Hz), 7.51 (dd, J=7 Hz, J=7 Hz, 1H), 8.06 (dd, J=7, J=7 Hz, 1H), 8.80 (s, 1H), 9.57 (d, J=7 Hz), 9.90 (s, 1H). MS: m/z 245.0683; required for C13H11NO4: 245.0688.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[CH:6][C:7]([C:11]([OH:13])=O)=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][NH2:53])[CH2:47][CH2:46]1>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([C:11](=[O:13])[NH:53][CH2:52][CH2:51][N:48]2[CH2:49][CH2:50][O:45][CH2:46][CH2:47]2)=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)O)nc1C
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)NCCN2CCOCC2)nc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of 5-acetyl-6-methyl-4-(3-nitrophenyl)-2-pyridinecarboxylic acid (0.95 g) in tetrahydrofuran (10 ml) was added N-hydroxybenzotriazole (0.43 g) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) at 5° C. After the mixture was stirred at the same temperature for 1 hour, 2-morpholinoethylamine (0.41 g) and triethylamine (0.32 g) was added thereto. The mixture was stirred at ambient temperature for 2 hours and diluted with ice-cold water (20 ml) and ethyl acetate (20 ml). The separated organic layer was washed with brine, dried and concentrated in vacuo. The residue was triturated with diethyl ether to give 3-acetyl-2-methyl-6-(2-morpholinoethylcarbamoyl)-4-(3-nitrophenyl)pyridine (0.45 g).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][NH:4][S:5](Cl)(=[O:7])=[O:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]([NH2:33])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]([NH:33][S:5]([NH:4][CH2:3][C:2]([F:10])([F:9])[F:1])(=[O:7])=[O:6])([CH3:31])[CH3:32])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)=[CH:16][CH:17]=1
Reactant: Cn1nc(-c2cccc(C(C)(C)N)c2)cc1-c1ccc(F)cc1
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(-c2cccc(C(C)(C)NS(=O)(=O)NCC(F)(F)F)c2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
2,2,2-Trifluoroethylsulfamoyl chloride (53 mg, 0.3 mmol) was added dropwise to a stirred solution of the amine from Step 4 (50 mg, 0.2 mmol) and Et3N (37 μL, 0.3 mmol) in CH2Cl2 (2 m]L) at RT under N2. The mixture was stirred at RT overnight and then diluted with CH2Cl2 (25 mL), washed with NaHCO3 solution (20 m L), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica eluting with 20% EtOAc/iso-hexane to yield the title sulfamide (5 mg, 6%). 1H NMR (CDCl3, 500 MHz) δ 8.02 (1H, s), 7.69 (1H, d, J=6.6 Hz), 7.45-7.42 (4H, m), 7.18 (2H, t, J=8.6 Hz), 6.58 (1H, s), 4.70 (1H, s), 4.30-4.27 (1H, m), 3.90 (3H, s), 3.57-3.53 (2H, m), 1.80 (6H, s). MS (ES+) C21H22F4N4O2S requires: 470, found: 471 (M+H+, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[C@H:14]12[CH2:20][C@H:17]([NH:18][CH2:19]1)[CH2:16][N:15]2[CH2:21][C@@H:22]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[OH:23].CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[OH:23][C@H:22]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:21][N:15]1[CH2:16][C@@H:17]2[CH2:20][C@H:14]1[CH2:19][N:18]2[S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3)ccc2c1COC2=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3S(=O)(=O)c2ccc(C#N)cc2)ccc2c1COC2=O

Procedure:
A solution of 4-cyanobenzene-1-sulfonyl chloride (31 mg, 0.12 mmol) in 0.3 mL of DMF was added to a solution of 5-((R)-2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride (32 mg, 0.10 mmol) (INTERMEDIATE 14) in 0.2 mL of DMF and DIEA (87 uL, 0.50 mmol). The combined solution was shaken for sixteen hours and then diluted with 0.5 mL DMSO. The resulting solution was purified by HPLC to afford 4-((1S,4S)-5-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-ylsulfonyl)benzonitrile.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:34][CH:33]=1
Reactant: COc1ccc(CCCN2CCCC[C@@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CCCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (39 mg, 0.99 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (6 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (178 mg, 0.90 mmol) was added to the suspension, and they were stirred at room temperature for 20 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-[3-(4-methoxyphenyl)propyl]homopiperidine (278 mg, 0.99 mmol) in dimethyl sulfoxide (3 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with hexane and ethyl acetate (3:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-[3-(4-methoxyphenyl) propyl]piperidine-2-ylmethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (196 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:25][C:26]1(OCCC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:23][CH3:24]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:26]3([O:25][CH2:22][CH2:23][CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCOC1(OCCC)CCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCC1
Yield: 37.6 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-propoxycycloheptane (2.14 g, 10 mmol) in the same manner as the example 20 to give the compound 27 (188 mg, 39.8%). PMR (CDCl3 -0.1% d5 -Py): δH0.87 (3 H, t, J 7.4 Hz, Pr) 1.24 (6 H, d, J 7 Hz, (CH3)2C), 3.00 (2 H, t, J 6 Hz, CH2 -Im), 3.05 (2 H, t, J 7 Hz, OCH2CH3), 3.09 (1 H, m, (CH3)2CH), 3.51 (3 H, s, NCH3), 3.71 (2 H, t, J 6 Hz, OCH2), 6.82 (2 H, d, J 1.6 Hz, arom-H), 7.11 (t-like, arom-H). IR(KBr)cm-1 : 3435, 3063, 1563, 1459, 1119, 1096, 1068, 1015. Elementary analysis (for C25H36N2O2Cl2S) Cacld.: C, 60.11% H, 7.26% N, 5.61% S, 6.42% Cl, 14.19% Found: C, 60.18% H, 7.30% N, 5.84% S, 6.55% Cl, 13.52%
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH:25]=[C:26](Br)Br)[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1.[CH3:32][NH:33][CH3:34].[OH2:35]>CN(C=O)C>[O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][C:26]([N:33]([CH3:34])[CH3:32])=[O:35])[N:22]=[N:21]4)[O:16][C:15]3=[O:29])=[CH:10][C:9]=2[F:30])[CH2:4][CH2:3]1
Reactant: CNC
Reactant: O=C1O[C@@H](Cn2cc(C=C(Br)Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reactant: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Yield: 36 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 25) (0.25 g, 0.43 mmol) was dissolved in DMF (1.5 ml). Dimethylamine (0.250 ml, 40% in water, 2.2 mmol) and water (0.25 ml) were added and the reaction mixture was heated for 3 hours to 90° C. It was cooled to room temperature and the solvent was removed under vacuum. Chromatography on silica gel with dichloromethane/methanol (20:1) gave 74 mg (36%) of the title compound as a colourless solid.
Reaction SMILES: [C:1]([C:8]1[NH:9][CH:10]=[CH:11]N=1)(C1NC=CN=1)=[O:2].[NH:13]1[CH2:18]COCC1.C1C[O:22]CC1>>[N:9]1([C:18]([NH2:13])=[O:22])[CH2:8][CH2:1][O:2][CH2:11][CH2:10]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: C1CCOC1
Reactant: C1COCCN1
Product: NC(=O)N1CCOCC1
Temperature: 65 °C
Yield: 33 %

Procedure:
Carbonyl diimidazole (32 mg, 0.2 mmol) was added to a stirred solution of the carboxylic acid (Example 24) (40 mg, 0.066 mmol) in THF (3 mL) under nitrogen at room temperature. The solution was heated at 65° C. for 3 hr. After cooling to room temperature, morpholine (9 μL, 0.1 mmol) was added and the mixture heated at 50° C. for 18 hr. The solution was concentrated to dryness in vacuo. 5% Citric acid solution was added and the mixture extracted with ethyl acetate three times. The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was pre-absorbed on silica gel and chromatographed (0-5% methanol/methylene chloride) to give the titled morpholino amide compound (15 mg, 33%) (for spectral data see Table VII).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:24][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.O>>[CH3:23][S:20]([C:17]1[N:16]=[CH:15][C:14]2[C:19](=[C:10]3[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[S:24][C:11]3=[CH:12][CH:13]=2)[N:18]=1)(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)c1cc2c(ccc3cnc(S(C)(=O)=O)nc32)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ncc2ccc3sc(C(=O)O)cc3c2n1
Yield: 98.8 %

Procedure:
2-Methanesulfonyl-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (4.20 g, 11.52 mmol) was placed in a 500 mL Florentine and cooled in an ice-bath. Pre-mixed TFA:DCM:water (1:1:0.025, 4.5 mL) was added in one portion and the resultant solution was stirred at 0° C. for 0.75 hours and a further 0.75 hours at room temperature. The reaction mixture was concentrated under reduced pressure and azeotroped with portions of DCM (5×50 mL) and Et2O (5×50 mL). The solid obtained was triturated with Et2O, filtered and washed with Et2O (3×5 mL) to give a light yellow powder (3.51 g, 99% yield). δH (d6 DMSO) 3.6-3.7(3H, s), 8.3(1H, d), 8.6(1H, d), 8.8(1H, s), 9.9-10.0(1H, s), 13.8-14.0(1H, br s)
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:15]
Reactant: Brc1ncccc1-c1cccnc1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ncccc1-c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of 16.46 g of 2'-bromo-3,3'-bipyridine, 24 ml of anhydrous hydrazine and 500 ml of dry pyridine was heated at 100° C. for 3 days. The solvent was removed under vacuum, toluene was added and removed and the residue was partitioned between saturated aqueous sodium carbonate and methylene chloride. The organic layer was dried, the solvent removed under vacuum and the residue crystallized from methylene chloride-hexane, giving 2'-hydrazino-3,3'-bipyridine as tan crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].C=O.[C:34]([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([CH:26]5[CH2:31][CH2:30][N:29]([CH3:34])[CH2:28][CH2:27]5)[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [BH3-]C#N
Reactant: Fc1ccc(Nc2ncnc3cnc(N4CCC(C5CCNCC5)CC4)nc23)cc1Cl
Agent: C=O
Agent: [Na+]
Product: CN1CCC(C2CCN(c3ncc4ncnc(Nc5ccc(F)c(Cl)c5)c4n3)CC2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(4-piperidinyl)-1-piperidinyl]pyrimido[5,4-d]pyrimidine by reductive amination with formaldehyde and sodium cyanoborohydride. Melting point: 159°-162° C.; Rf : 0.58 (alumina; petroleum ether/ethyl acetate/methanol=10:10:1)