Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:26]1([S:32]([N:1]2[C:9]3[C:4](=[C:5]([O:10][CH2:11][C@@H:12]4[CH2:16][CH2:15][CH2:14][N:13]4[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A stirred solution of t-butyl (2S)-2-[(1H-indol-4-yloxy)methyl]-1-pyrrolidinecarboxylate (1.23 g, 3.89 mmol) in THF is treated with sodium hydride (0.17 g, 60% in mineral oil, 4.28 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with benzenesulfonyl chloride (0.55 mL, 4.28 mmol), stirred at room temperature for 22 h, quenched with ice-water and diluted with EtOAc. The organic phase is separated, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (siliga gel, EtOAc/hexanes, 2/8) to afford the title compound as an off-white foam, 1.21 g, mp 48-50° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH:20]([C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1)[C:21]#[N:22]>>[C:21]([CH:20]([C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1)[NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])#[N:22]
Reactant: CC1(C(N)C#N)COC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC1(C(C#N)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c) and 2-amino-2-(3-methyloxetan-3-yl)acetonitrile (example 251b) as starting materials and isolated (105 mg, 85%); MS (ESI, m/z): 370.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH:25](O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(C(=O)OCc3ccccc3)c1)N2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)OCc3ccccc3)c1)N2
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a solution of methyl 2-(3-(benzyloxycarbonyl)phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (14.0 g, 31.4 mmol, 1.0 eq.), triethylsilane (10.6 g, 91.4 mmol, 2.91 eq.) in dichloromethane (240 mL), which was placed in a drop funnel, under nitrogen below 0° C. over 1 h. colorless solution turned yellow gradually. The resulting mixture was allowed to warm back to room temperature naturally overnight. Thin layer chromatography (Petroleum ether:ethyl acetate=3:1) showed the reaction was complete. The reaction mixture was basified with solid sodium carbonate to pH=7 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (Petroleum ether: ethyl acetate=10:1) to give 10.2 g of methyl 2-(3-(benzyloxycarbonyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow oil, yield: 75.6%. MS (ESI+APCI) M+1=430.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44].C(=O)([O-])[O-].[Na+].[Na+].O>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.O1CCCC1>[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:4]2[CH:5]=[C:6]([Cl:32])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C@H:14]4[CH2:15][CH2:16][C@@H:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:29])[CH3:30])[CH2:18][CH2:19]4)[C:10]3=[O:31])=[C:2]([Cl:1])[CH:3]=2)=[CH:47][CH:46]=1)=[O:44]
Reactant: CC(C)[Si](O[C@H]1CC[C@@H](N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C

Procedure:
Bubble nitrogen through a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-cis-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-phenyl ester (12.2 g, 18.87 mmol), 4-methoxycarbonylphenylboronic acid (4.1 g, 22.64 mmol), sodium carbonate (6 g, 56.6 mmol), 50 mL water, and 150 mL tetrahydrofuran for 30 min at room temperature. Add tetrakis(triphenylphosphine)palladium (1.7 g, 1.47 mmol) by weighing into a nitrogen filled vial and transferring the material as a dry solid to the reaction flask. Sparge an additional 5 min, then heat at 80° C. 1 hr. Dilute with 50 mL each of water and ethyl acetate, separate layers and extract the aqueous layer with 25 mL ethyl acetate. After combining the organic layers, wash with 50 mL brine, dry over magnesium sulfate and concentrate under vacuum. Purify on silica by eluting with 10-30% ethyl acetate in hexanes to give 11.1 g (93%) of product as an ivory foam: MS (m/z): 632 (M+).
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]([NH:15][C:16](=[NH:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5].Cl.[CH3:22][O:23][C:24]1[CH:57]=[CH:56][C:27]([CH2:28][S:29][C@@H:30]2[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[C@H:32]([C:48]([N:50]3[CH2:55][CH2:54]N[CH2:52][CH2:51]3)=[O:49])[CH2:31]2)=[CH:26][CH:25]=1>CO>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][S:29][C@@H:30]2[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[C@H:32]([C:48]([N:50]3[CH2:55][CH2:54][N:18]([C:16](=[N:15][C:13]([O:12][CH2:11][C:10]4[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:20][CH:19]=4)=[O:14])[CH3:17])[CH2:52][CH2:51]3)=[O:49])[CH2:31]2)=[CH:56][CH:57]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 33.3 %

Procedure:
11 ml of methylene chloride, followed by 452 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine, were added to a solution of 1.1 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (ii) above] in 22 ml of methanol, whilst heating the solution under reflux. The resulting mixture was then heated under reflux for a further 4 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent to give 466 mg of the title compound, as a powder.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH:12]([CH3:14])[CH3:13].[OH-].[Na+]>CO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([NH:11][CH:12]([CH3:14])[CH3:13])=[C:4]([CH:9]=1)[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1cc(Cl)ccc1NC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.2 %

Procedure:
To a solution of 480 mg of 5-chloro-2-isopropylamino-benzoic acid methyl ester in methanol (5 ml) were added 3.16 ml of a 1N NaOH solution and the mixture was stirred for 4 d at RT. Then the reaction mixture was concentrated in vacuo and the remaining residue dissolved in water. The resulting solution was washed with ethyl acetate and then the pH was adjusted to 1 with 1N HCl solution and the mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the title compound as an off-white solid (429 mg, 95%). NMR (CDCl3, 300 MHz): δ 1.27 (d, J=6.3 Hz, 6H), 3.70 (sept, J=6.3 Hz, 1H), 6.65 (d, J=9.1 Hz, 1H), 7.31 (dd, J=9.1 and 2.7 Hz, 1H), 7.92 (d, J=2.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[C:6]([CH:10]=1)[C:7]([O:9][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)=[O:8]
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(F)cc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Temperature: 50 °C

Procedure:
To a solution of 5-bromo-2-hydroxy-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 5; 720 mg, 2.28 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (1102 mg, 7.97 mmol) and 4-fluorobenzyl bromide (0.62 ml, 5.01 mmol). The mixture was heated at 50° C. for 2 hours, cooled and the solvent removed in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (15 ml). The organic layer was separated, washed further with water (2×5 ml), dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by column (SiO2, 6:1-1:1 cyclohexane/ethyl acetate) gave the product as a pale yellow oil. 544 mg.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:29][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccc(F)cc1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccc(F)cc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-fluoro-phenyl)-C-phenyl-methylamine (CA [55095-26-6]).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@H:7]([CH3:10])[CH:8]([OH:9])[C:30]#[C:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)Oc1ccc(Br)cc1
Reactant: C#Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1

Procedure:
Prepared according to the method described in Example 1c) from (2S)-2-(4-bromophenoxy)propan-1-ol (9.24 g, Example 4b)), oxalyl chloride (4.38 ml), dimethyl sulfoxide (4.4 ml), triethylamine (22.4 ml), 3-pyridylacetylene (6.3 g) andn-butyllithium (2.5M in hexanes, 24 ml) to give the sub-title compound as an oil and as a 4:1 mixture of diastereomers (8.31 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)=[C:6]([N+:18]([O-])=O)[CH:5]=1>CO.[Ni]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(Nc2ccnc(Br)c2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1ccc(Nc2ccnc(Br)c2)c(N)c1
Reaction time: 3 h

Procedure:
4-(2-Bromo-pyridin-4-ylamino)-3-nitro-benzoic acid methyl ester 3 (6 g; 17 mmol) was dissolved in MeOH (200 ml) and Raney-nickel (0.6 g; 4.5 mmol) was added and subsequently hydrogenated under an atmosphere of H2 for 3 h. LCMS showed full conversion and the reaction mixture was filtered through a bed of Celite to remove the catalyst. Thorough washing with MeOH followed by evaporation of the solvent under educed pressure gave 4 as a brown solid. Yield 3.2 g; 60%. The product identity was confirmed by NMR and LCMS and taken for the next step.
Reaction SMILES: [C:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[S:26])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=S)c1ccc([N+](=O)[O-])cc1
Yield: 68 %

Procedure:
The preparation of Example 1 was repeated with the changes that N-tert-butyl 4-nitrobenzamide (3.00 g, 0.0135 mole) and 2,4-bis (4-methoxyphenyl) -1,3 -dithia-2,4-diphosphetane-2,4-disulfide (3.28 g, 0.0081 mole) were the starting reactants and the reaction was carried out by refluxing in 50 mL dry toluene solvent for 3 hours. In addition, the solvent was removed in vacuo leaving a yellow viscous oil. The oil was taken up into ethyl acetate and the solution filtered through silica gel. The solvent was removed in vacuo, the residue taken up into ethanol, and the mixture filtered through fluted filter paper. Recrystallization from ethanol produced 2.20 g golden crystals of the desired product (68% yield), mp 136°-138° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 8.21 ppm (d, 8.0 Hz, 2H; 3,5-aryl H); 7.76 ppm (d, 8.0 Hz, 2H; 2,6-aryl H); 1.67 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:41])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[ClH:42]>O1CCOCC1>[ClH:42].[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:41])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c(CCCC(=O)O)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c(CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
To a solution of (S)-9-Bromo-5-[p-tert-butoxycarbonylaminomethyl-o-(3-carboxypropyl) phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (103 mg, 0.164 mmol)in 1,4-dioxane (5 mL) was added 4N hydrogen chloride in 1,4-dioxane (5 mL) at room temperature. The mixture was stirred for 20 h at room temperature and concentrated. The residual solid was dried in vacuo to give 90 mg of the title compound (97%).
Reaction SMILES: CN(C)C=O.[Cl:6][CH:7](Cl)[CH3:8].C(Cl)(=O)C(Cl)=O.[N:16]1[C:21]2[CH:22]=[CH:23][S:24]C=2C(=O)[NH:18][CH:17]=1>O>[Cl:6][C:7]1[C:8]2[S:24][CH:23]=[CH:22][C:21]=2[N:16]=[CH:17][N:18]=1
Reactant: O=c1[nH]cnc2ccsc12
Reactant: CC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2ccsc12
Reaction time: 2.5 h
Yield: 99 %

Procedure:
After dimethylformamide (15.4 ml, 197.13 mmol) was added into 150 ml of dichloroethane with lowering the temperature to 0° C., oxalyl chloride (25 4 ml, 295.70 mmol) was slowly added. When white gel type started to form, 3H-thieno[3,2-d]pyrimidine-4-one (15 g, 98.57 mmol) was added. After 2.5 hours of reflex of the reaction mixture, the temperature was lowed to room temperature. After adding water, the reaction mixture was extracted using dichloromethane (3×300 ml) and dried with anhydrous magnesium sulfate. After concentrated under vacuum, trituration was carried out with 200 ml of hexane and the title compound (16.7 g, 99%) was obtained as a dark brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCNC(C)=O)c2c1
Solvent: ClCCl
Product: CC(=O)NCCc1cccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethyl sulphide complex are dissolved in 100 ml of dichloromethane and stirred for 15 minutes at ambient temperature. A solution of 13.7 mmol of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethane is added, and the reaction mixture is heated at reflux for 30 hours. After cooling, the reaction mixture is cautiously hydrolysed and the dichloromethane is evaporated off. The mixture is then extracted with ethyl acetate and the combined organic phases are washed with an aqueous 1M potassium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and concentrated to yield the title compound. White solid.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[OH:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:11]([C:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cn1cc(-c2ccc3ncc(C(O)c4c(F)cc5ncccc5c4F)n3n2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1cc(-c2ccc3ncc(C(=O)c4c(F)cc5ncccc5c4F)n3n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-(5,7-Difluoro-quinolin-6-yl)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanol (Stage 191.3, 1.0 g, 2.55 mmol) was dissolved in DCM (25.5 mL) and Dess-Martin periodinane (1.621 g, 3.82 mmol) was added. The RM was stirred for 1 h at rt and then 2.5 M NaOH solution was added. The RM was extracted with EtOAc/MeOH (9:1) twice. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by MPLC with DCM and MeOH to afford a light yellow solid as the title compound (tR 1.2 min (conditions 2), MH+=391)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[NH:11][C:12](=[O:16])[CH:13]([CH3:15])[O:14][C:9]=2[CH:8]=1.[CH3:27]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:27])[C:12](=[O:16])[CH:13]([CH3:15])[O:14][C:9]=2[CH:8]=1
Reactant: CI
Reactant: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
First, 60% sodium hydride (0.2 g) was suspended in dimethylformamide (5 ml), and a solution of 7-(2-chloro -4-trifluoromethylphenoxy)-2-methyl-2H-1,4-benzoxazine-3 (4H)-one (0.4 g) prepared in Example 1 in dimethylformamide (5 ml) was dropwise added thereto while cooling with ice, and the mixture was stirred for 10 min. Then methyl iodide (0.7 g) was added thereto and the mixture was stirred for additional 10 min, and thereafter, water (20 ml) was added thereto to terminate the reaction. The reaction mixture was extracted with ethyl acetate (50 ml×2), washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to prepare the title compound (0.4 g) as a colorless crystal (yield: 98%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[CH3:16]O>>[OH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:16])=[O:10])=[O:6]
Reactant: CO
Reactant: O=C(O)CCC(=O)c1ccccc1O
Agent: Cl
Product: COC(=O)CCC(=O)c1ccccc1O
Temperature: 0 °C
Yield: 98 %

Procedure:
Hydrogen chloride was bubbled into a gently boiling solution of the known 3-(2-hydroxybenzoyl)propionic acid (10 g, 0.05 mole) in dry methanol (20 ml) until esterification was complete. The solution was poured into ice-water and the ester extracted into dichloromethane. The organic solution was washed with water and evaporated to give methyl 3-(2-hydroxybenzoyl)-propionate (10.55 g. 98%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12]C(=O)OC(C)(C)C)[CH2:7]1)#[N:2].C(O)(C(F)(F)F)=O>>[NH2:12][C@@H:8]1[CH2:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[C:1]#[N:2])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(Cc2ccccc2C#N)C1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1CN1CCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a microwave vial equipped with a stir bar was added tert-butyl [(3R)-1-(2-cyanobenzyl)piperidin-3-yl]carbamate (1000 mg, 3.17 mmol) and TFA (1000 μl, 12.98 mmol). The reaction was stirred at room temperature for 30 minutes. The LCMS taken after 30 minutes indicates formation of the desired product. The crude reaction mixture was concentrated in vacuo, and was then dissolved in ethyl acetate and filtered through a sodium bicarbonate filter. The combined organics were concentrated under reduced pressure. The material was dissolved in acetonitrile and water, and was dried on the lyophilizer overnight.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Cl:10])[N:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[Cl:10][CH2:9][C:5]1[N:4]=[C:3]([CH2:2][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1cccc(CCl)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(CCl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
2,6-Bis(chloromethyl)pyridine (352 mg) was suspended in 4 mL of ethanol, and 372 mg of N-(t-butoxycarbonyl)piperazine was added into the suspension at ice temperature, and then the suspension was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was added to water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by chromatography on silica gel (methylene chloride-ethanol=30:1) to give 250 mg of t-butyl 4-(6-chloromethylpyridin-2-ylmethyl)piperazine-1-carboxylate as a colorless oil.