Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]=[C:8]([NH2:20])[C:9]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:10]=3[NH:11][C:5]=2[CH:4]=1.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][C@H:28]1[CH2:33]N[CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CS(C)=O>[F:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]=[C:8]([N:20]3[CH2:31][CH2:30][NH:29][C@@H:28]([CH2:27][CH2:26][CH2:25][O:24][CH3:23])[CH2:33]3)[C:9]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:10]=3[NH:11][C:5]=2[CH:4]=1
Reactant: COCCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccc(F)cc2Nc2ccc(C(F)(F)F)cc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3ccc(C(F)(F)F)cc32)CCN1
Temperature: 110 °C
Reaction time: 24 h
Yield: 51.2 %

Procedure:
Combine 7-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.399 g, 1.20 mmol), (S)-2-(3-methoxy-propyl)-piperazine (0.381 g, 2.41 mmol), and diisopropylethyl amine (0.21 mL, 1.20 mmol) in a mixture of toluene (4.5 mL) and dimethylsulfoxide (1.5 mL) and stir at 110° C. for 24 hours. Evaporate the mixture then purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 7% 2N ammonia-methanol in dichloromethane gives (s)-7-fluoro-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine (0.268 g, 0.614 mmol, 51%) as a yellow oil. Mass spectrum (APCI): m/z=437.2 (M+1).
Reaction SMILES: [NH2-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.Cl[CH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH:4]1[N:12]([CH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(NC2Cc3ccccc3C2)cc1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCCC1CCN(c1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of sodamide (256 mg, 6.58 mmol) in toluene (10 mL) was added a solution of indan-2-yl-phenyl-amine (7; 1.0 g, 4.78 mmol) in toluene (5 mL) at 0° C. The reaction mixture was stirred at rt for 3 hours. A solution of 2-(2-chloroethyl)-1-methyl-pyrrolidine hydrochloride (18; 0.808 g, 4.39 mmol) in toluene (5 mL) was added to the reaction mixture and the resulting mixture was refluxed for 16 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography on neutral alumina eluting with 0.8% methanol-DCM to provide compound 19.
Reaction SMILES: [CH2:1]([C:3]1[C:8](/[CH:9]=[CH:10]/[O:11]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=2)[C:23]#[N:24])=[N:15][CH:14]=1)[CH3:2].Cl>O1CCCC1>[CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=[O:11])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:28])[CH3:29])=[C:22]([CH:25]=2)[C:23]#[N:24])=[N:15][CH:14]=1)[CH3:2]
Reactant: CCc1c(/C=C/OC)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 75 °C
Yield: 100 %

Procedure:
To a mixture of 5-(5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D75) (550 mg) in tetrahydrofuran (THF) (20 mL) under nitrogen was added HCl (1.360 mL). The reaction was heated to 75° C. for 6 h. The mixture was concentrated to give the crude product 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile (D76) (531 mg) as a brown oil. MS (ES): C23H22N2O2S requires 390. found 391.0 (M+H+).
Reaction SMILES: [I:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@H:4]1[OH:17].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:17][C@H:4]1[C@@H:3]([CH2:2][I:1])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn([C@H]2C[C@@H](O)[C@@H](CI)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CI
Temperature: 25 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
To a stirred solution of 1-(2,5-dideoxy-5-iodo-β-D-threo-pentofuranosyl)thymine (for preparation see ref. J. Org. Chem. 1964, 29, 2076) (5.1 g, 14.5 mmol) in anhydrous pyridine (50 mL) at 0° C. under argon was added acetic anhydride (7.0 ml, 75.4 mmol). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was cooled with ice bath and quenched by slow addition of water (15 mL). The reaction mixture was stirred for 30 min and concentrated to dryness, and co-evaporated with anhydrous toluene three times. The residue was re-dissolved in dichloromethane and chromatographed on silica gel with 1-3% methanol in ethyl acetate gave 4.4 g of 1-(3-O-acetyl-2,5-dideoxy-5-iodo-β-D-threo-pentofuranosyl)thymine (49).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1.CC1C=CC(C)=CC=1>[N+:16]([C:12]1[CH:11]=[C:10]([C:9]2[S:21][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(Nc1cnccc1O)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: Cc1ccc(C)cc1
Product: O=[N+]([O-])c1cccc(-c2nc3cnccc3s2)c1
Temperature: 140 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
A mixture of N-(4-hydroxypyridin-3-yl)-3-nitrobenzamide (1.33 g, 5.2 mmol) and P2S5 (2.40 g, 10.4 mmol) in pyridine (6.0 mL) and p-xylene (24 mL) was stirred at 140° C. for 18 h. The solvent was removed under vacuo while hot and the residue was purified by recrystallization from EtOH to afford 2-(3-nitrophenyl)thiazolo[4,5-c]pyridine as a yellow solid (1.08 g, yield: 81%). MS (ESI) calcd. for C12H7N3O2S (m/z): 257, found: 258 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:13][O:12][C:9]1[N:8]=[CH:7][C:6]([NH:5][CH2:4][C:3]([OH:14])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)CNc1ccc(OC)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(NCC(=O)O)cn1
Reaction time: 3 h

Procedure:
To a solution of (6-methoxy-pyridin-3-ylamino)-acetic acid methyl ester, 113 mg (0.58 mmol) in 10 mL of dioxane was added a solution of 70 mg (2.9 mmol) of lithium hydroxide in 10 mL of water. The reaction mixture was stirred for three hours, acidified to pH=1 with 5 N HCl and concentrated to dryness to yield the crude desired product which was carried on without further purification. MS (IS) 183.1 (M+1).
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][S:32]([CH:35]6[CH2:37][CH2:36]6)(=[O:34])=[O:33])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].O1CCOCC1>CN(C=O)C>[C:20]1([C:23]23[CH2:24][CH2:25][C:26]([NH:31][S:32]([CH:35]4[CH2:37][CH2:36]4)(=[O:33])=[O:34])([CH2:27][CH2:28]2)[CH2:29][CH2:30]3)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:22][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S(=O)(NC12CCC(c3nnc4cnc5[nH]ccc5n34)(CC1)CC2)C1CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A round bottom flask was charged with N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.27 g, 0.50 mmol), aqueous NaOH (1N, 1.0 mL, 1.0 mmol), and 1,4-dioxane (8 mL). The reaction mixture was stirred at about 60° C. for about 2 h. NH4OAc (50 mM aqueous buffer, 2 mL) and DMF (7 mL) were added and insoluble material was removed via filtration. The filtrate was purified by RP-HPLC (Table 2, Method c). The appropriate fractions were combined, the organic solvent was concentrated under reduced pressure, the resulting solid was collected by filtration, washed with water (20 mL), and lyopholized to give N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide as a solid (0.11 g, 56%): LC/MS (Table 2, Method a) Rt=1.53 min; MS m/z 387 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:34])[NH:26][C:27]([CH2:31][CH2:32][CH3:33])=[CH:28][C:29]=1[CH3:30].C(O)(C(F)(F)F)=O.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:11]=[C:12]([C:13]([NH:22][CH2:23][C:24]3[C:25](=[O:34])[NH:26][C:27]([CH2:31][CH2:32][CH3:33])=[CH:28][C:29]=3[CH3:30])=[O:15])[C:7]=2[CH:6]=[N:5]1)[CH3:3]
Reactant: CCCc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1-(1-Methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (192 mg, 0.680 mmol), 3-(aminomethyl)-4-methyl-6-propyl-2(1H)-pyridinone.TFA (200 mg, 0.680 mmol), HOAT (139 mg, 1.019 mmol), EDC (195 mg, 1.019 mmol), and N-methylmorpholine (0.299 mL, 2.72 mmol) were sequentially added to DMF(6 mL), and the mixture stirred at 40° C. overnight. The reaction mixture was then filtered. The collected solid was washed with ethanol, and dried, affording the final product as a white solid, 0.160 g (53%). LCMS E-S (M+H)=445.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, 3 H), 1.46-1.65 (m, 8 H), 2.24 (s, 3 H), 2.38 (t, J=7.58 Hz, 2 H), 4.43 (d, J=4.80 Hz, 2 H), 5.37 (s, 1 H), 5.93 (s, 1 H), 8.23 (d, J=5.81 Hz, 2 H), 8.30 (s, 1 H), 8.45 (s, 1 H), 8.78 (d, J=5.31 Hz, 2 H), 9.00 (br. s., 1 H), 11.56 (s, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([CH3:14])([CH2:12][NH2:13])[CH2:10][NH2:11]>N1C=CC=CC=1>[NH2:11][CH2:10][C:9]([CH3:14])([CH3:8])[CH2:12][NH:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(CN)CN
Reactant: Fc1ccccn1
Solvent: c1ccncc1
Product: CC(C)(CN)CNc1ccccn1

Procedure:
A mixture of 2-fluoropyridine and 2,2-dimethyl-1,3-propanediamine (2 eq) in pyridine (0.3M) was refluxed for 18 hrs. and then concentrated by rotary evaporation. The solution was then concentrated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated, and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography using 10:1:1 EtOH/NH4OH/H2O as eluent. EI-MS m/z 180 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[CH2:13]=[C:14](B(O)O)[CH3:15].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Br:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([C:14]([CH3:15])=[CH2:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)cc(Br)c1
Reactant: C=C(C)B(O)O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1,3-dibromo-5-(trifluoromethyl)benzene (3.03 g, 10 mmol) in dioxane (20 mL) was added Pd(PPh3)4 (300 mg, 0.26 mmol), prop-1-en-2-ylboronic acid (1.0 g, 12 mmol), K2CO3 (2.8 g, 20 mmol) and water (1 mL) under N2. The mixture was stirred at 90° C. overnight, concentrated and purified by CC (hexane) to afford compound P28a (1.9 g, 71%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>ClCCl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:40][C:41]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]3[N:14]4[N:15]=[C:16]([NH:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]6[CH2:29][CH2:30][CH2:31][CH2:32]6)=[CH:21][CH:20]=5)[N:17]=[C:13]4[CH:12]=[CH:11][CH:10]=3)[CH:4]=2)=[O:42])[CH:37]=[CH:38][CH:39]=1
Reactant: NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1)Nc1cccc(Cl)c1
Reaction time: 8 h

Procedure:
[5-(3-Aminomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (40 mg, 0.093 mmol) was dissolved in dichloromethane (1 ml). 3-Chlorophenyl isocyanate (13 μl, 0.103 mmol) was added and the mixture stirred overnight. The solvent was removed under reduced pressure and the product was purified by preparatory HPLC to give the desired product. LCMS RT: 2.86 min, MI: 582, Method: 2. 1H NMR (DMSO, 300 MHz): 9.38 (s, 1H), 8.99 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.86 (d, 1H), 7.66-7.49 (m, 5H), 7.17 (d, 2H), 7.11 (d, 1H), 7.01 (t, 1H), 6.84 (d, 2H), 4.39 (d, 2H), 3.98 (t, 2H), 2.81 (t, 2H), 2.53 (s, 4H), 1.67 (s, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][OH:11])=[O:4].[H-].[Na+].O>O1CCCC1>[CH2:10]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[C:3](=[O:4])[CH2:2][O:11]1
Reactant: O=C(CCl)N1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1COCC2CCCN12
Reaction time: 14 h

Procedure:
(S)-1-(Chloroacetyl)-2-pyrrolidinemethanol, 12 g (0.068 mol), is dissolved in 500 ml of tetrahydrofuran, the solution is cooled to 0°-5° C., and 3.96 g (0.099 mol) of 60% sodium hydride in mineral oil dispersion is slowly added. The mixture is allowed to reach room temperature and is stirred for 14 hours. Water, 20 ml, is added, the solvents evaporated in vacuo, and the residue suspended in 300 ml of chloroform and washed with 100 ml of water and then a saturated aqueous solution of sodium chloride, 2×200 ml. The chloroform layer is separated, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4-(3H)-one, 4.4 g; mp 63.5°-66°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][C:20]=1[NH2:31])[CH3:16].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(N(CC)CC)C>[CH3:15][O:13][C:12]([C:3]1[C:2]([NH2:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[O:14].[CH2:15]([O:17][C:18](=[O:32])[C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][C:20]=1[NH2:31])[CH3:16]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc2ccccc2cc1N
Reaction time: 12 h

Procedure:
3-Amino-naphthalene-2-carboxylic acid (compound A′) (1.2 g) was dissolved in anhydrous methylene chloride (12 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5 g), 1-hydroxybenzotriazole monohydrate (1.5 g), and triethylamine (1 ml) were added to the solution at room temperature, and the mixture was then stirred at that temperature for 12 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 3-amino-naphthalene-2-carboxylic acid methyl ester as a useful intermediate (compound A) (530 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: NCCc1cccs1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCc1cccs1)c1cc(Cl)ccc1Cl
Yield: 66.7 %

Procedure:
Reaction of 2,5-dichlorobenzoic acid (164 mg, 0.85 mmol) in thionyl chloride (2 mL) then with 2-thiopheneethylamine (50 μL, 0.42 mmol) in presence of triethylamine (0.5 mL) in THF (3 mL) according to method B gave 2,5-dichloro-N-(2-thiophen-2-yl-ethyl)-benzamide (83 mg, 0.28 mmol, 66% yield) as a off-white powder after purification on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].Cl.[N:28]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][N:30]=[N:29]1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:35]2[CH2:36][CH2:37][CH:33]([N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[CH2:34]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Reactant: c1cn(C2CCNC2)nn1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Solvent: CC#N
Product: Nc1c(F)c(N2CCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 56.9 %

Procedure:
A mixture of 5-amino-1-(2,4-difluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (200 mg, 0.54 mmol), 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (231 mg, 1.25 mmol) and diazabicycloundecane (200 mg, 1.31 mmol) in acetonitrile (25 ml) was refluxed for 45 h. The separated solid was filtered, washed with acetonitrile and ether to give 150 mg (57%) of desired product, m.p. 307.5°-309° C. 1H NMR (TFA) δ: 2.81 (m, 2H), 4.06-4.53 (m, 4H), 5.73 (m, 1H), 7.15-7.23 (m, 2H), 7.59-7.66 (m, 1H), 8.52 (d, 1H), 8.62 (d, 1H), 8.82 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:18][C:19]1=[O:21]
Reactant: COc1cc(Cl)c(Nc2ccccc2CC(=O)O)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1Cc2ccccc2N1c1c(Cl)cc(O)cc1Cl
Temperature: 180 °C

Procedure:
The 2-[(2,6-dichloro-4-methoxyphenyl)amino]phenylacetic acid (0.1 mol) from example 23 was added in portions to a melt of 200 g of pyridine hydrochloride (1.75 mol) at 170° C. The mixture was heated at 180° C. for 3 h and poured onto 2000 ml of ice water while hot. The precipitated product was filtered off, washed with water, and dissolved in 1000 ml of ethyl acetate. The organic phase was washed with 200 ml of 1N HCl in water (2×100 ml) and evaporated to give N-(2,6-dichloro-4-hydroxyphenyl)oxindole. To a solution of 8 g of N-(2,6-dichloro-4-hydroxyphenyl)-oxindole in 200 ml of n-butanol were added 7 g of NaOH and 1 g of KOH, and the reaction mixture was refluxed for 24 h and evaporated in vacuo. The residue was dissolved in 700 ml of water and the aqueous solution was extracted with ether (2×200 ml), cooled to 0° C., and acidified with concentrated HCl. The precipitate was taken up in 300 ml of ether. The organic phase was washed with 30 ml of water, 0.5N NaHCO3 (5×80 ml), and 80 ml of 2N KHCO3 solution. The combined NaHCO3 extracts were cooled to 0° C. and acidified with 2N HCl, and the precipitate was dissolved in 200 ml of ether. The organic layer was washed with 30 ml of water and evaporated to yield 2-[(2,6-dichloro-4-hydroxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH:19][C@@H](C3C=CC=CC=3)C)[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3].[H][H]>[Pd].CO>[ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH2:19])[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3]
Reactant: CCOc1cc([C@H]2CSCC[C@H]2N[C@H](C)c2ccccc2)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOc1cc([C@H]2CSCC[C@H]2N)ccc1OC
Reaction time: 5 h

Procedure:
A mixture of 3.6 g of 10% Pd catalyst on charcoal and 4 mmol of (3R,4R)-3-(3-ethoxy-4-methoxyphenyl)-N-[(1R)-1-phenylethyl]tetrahydro-2H-thiopyran-4-amine hydrochloride in 100 ml of methanol is hydrogenated with 110 mbar hydrogen pressure at reflux temperature for 5 h. Additional 3.6 g of the Pd catalyst are added and the hydrogenation is continued for further 5 h. The catalyst is filtered off and the filtrate concentrated yielding the title compound as a highly viscous resin which is used for the next reaction steps without further purification.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][CH2:8][CH:9]([OH:25])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)(=[O:3])[NH2:2].[C:30](OC(=O)C)(=[O:32])[CH3:31].[OH-].[Na+]>N1C=CC=CC=1>[C:1]([CH2:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[O:7][CH2:8][CH:9]([O:25][C:30](=[O:32])[CH3:31])[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)(=[O:3])[NH2:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1N1CCN(CC(O)COc2ccccc2CC(N)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccccc1N1CCN(CC(COc2ccccc2CC(N)=O)OC(C)=O)CC1
Temperature: 0 °C

Procedure:
Two grams of 1-(2-carbamoylmethylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol are added to 20 ml. of anhydrous pyridine, followed by the immediate addition of 8.0 g. of acetic anhydride with stirring. The resulting solution is refluxed for a period of 5 minutes, cooled and subsequently poured into 50 ml. of ice water, basified with 2N aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is then washed with water, dried over anhydrous sodium sulfate and evaporated to yield the crude product. After recrystallization from ethanol, there is obtained pure 1-(2-carbamoylmethylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-acetoxypropane as final product.