Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][NH:21][CH3:22])[CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].C(=O)([O-])O.[Na+]>ClCCl>[C:36]([N:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][N:17]=1)[C:13]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:23])[CH3:22])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CNCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(CN(C)C(C)=O)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide (207 mg, 0.5 mmol) is dissolved in dichloromethane (10 ml) and treated with pyridine (0.07 ml, 0.85 mmol) and acetyl chloride (0.05 ml, 0.7 mmol) and stirred for 16 h at ambient temperature. Saturated aqueous sodium hydrogen carbonate (10 ml) is added, the layers are separated and the aqueous phase extracted twice with each 10 ml dichloromethane. The combined organic phases are dried with magnesium sulfate and evaporated. Recrystallization from ethyl acetate afforded the title compound as light-yellow solid (80% yield), mp 228-230° C. MS: m/e=456 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](I)[C:3]=1[CH:10]([OH:28])[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[CH2:12].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[C:10](=[O:28])[CH:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]3)[CH2:15][CH2:14]1)[CH2:12]2
Reactant: C=C(C1CCC(C2CCC(CCC)CC2)CC1)C(O)c1c(F)cc(C)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCC1CCC(C2CCC(C3Cc4cc(C)cc(F)c4C3=O)CC2)CC1
Temperature: 25 °C

Procedure:
75 g (0.15 mol) of 1-(2-fluoro-6-iodo-4-methylphenyl)-2-(4′-propyl-bicyclohexyl-4-yl)-prop-2-en-1-ol, 50 ml of triethylamine, 400 mg of palladium(II) acetate (1.8 mmol) and 960 mg (3.7 mmol) of triphenylphosphine are dissolved in 200 ml of acetonitrile and refluxed overnight. The mixture is cooled down to room temperature and subjected to conventional workup.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].O.[Cl-].[C:14]1([N+:20]#[N:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([NH:20][N:21]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#[N+]c1ccccc1
Reactant: CC(=O)CC(=O)OCC(C)C
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(=O)OCC(C)C
Yield: 88.1 %

Procedure:
15.8 g (0.1 mol) of i-butyl acetoacetate, 12 g (0.146 mol) of CH3 COONa, 20 ml of water, 75 ml of ethanol and a solution of 0.1 mol of phenyldiazonium chloride were treated as described in preparation 2. The precipitated solid was filtered an dried in vacuo yielding 23.1 g of the title compound. M.p.=45°-50° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)([OH:3])=[O:2].[CH2:27](O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:24][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:25])[C:18]=1[CH2:17][C:16]([C:10]1[C:9]2[C:5]([CH2:4][C:1]([O:3][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:2])=[CH:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:26]
Reactant: OCCc1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)OCCc3ccccc3)coc12
Yield: 36 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 151 (0.30 g) obtained in Example 151 and phenethyl alcohol (0.07 ml) to give Compound 153 (0.14 g, 36%) as white crystals.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([SH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH2:10]([O:17][C:18](ON1C(=O)CCC1=O)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CO>[CH2:10]([O:17][C:18]([NH:1][C@@H:2]([C:6]([SH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a round bottom flask was added (R)-2-amino-3-mercapto-3-methylbutanoic acid (5.06 g, 33.9 mmol), N-(benzyloxycarbonyloxy)succinimide (8.87 g, 35.6 mmol), MeOH (50 mL) followed by DIPEA (11.9 mL, 67.8 mmol). The reaction was stirred at rt for 1 hr. The reaction was concentrated and the residue was diluted with EtOAc (120 mL). The organics was washed with water (2×50 mL) and saturated aqueous NaCl (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give (R)-2-(benzyloxycarbonylamino)-3-mercapto-3-methylbutanoic acid (4.78 g, 16.9 mmol, 49.7% yield) as a clear oil. Anal. Calcd. for C13H17NO4S m/z 283.3. found: 282.3 (M−H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.45-7.30 (m, 5H), 6.09-5.84 (m, 1H), 5.20-5.01 (m, 2H), 4.37-4.18 (m, 1H), 1.53 (br. s., 3H), 1.39 (br. s., 3H); 13C NMR (126 MHz, CDCl3) δ ppm 156.43, 136.49, 128.44, 128.28, 128.02, 53.12, 41.51, 30.83, 29.72, 11.64.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(OC([N:18]=[C:19]=S)=O)C.Cl.[NH2:22]O>>[Br:1][C:2]1[C:3]2[N:4]([N:22]=[C:19]([NH2:18])[N:12]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NO
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)N=C=S
Agent: Cl
Product: Nc1nc2c(Br)cc(C(F)(F)F)cn2n1

Procedure:
8-Bromo-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 3-bromo-5-trifluoromethyl-pyridin-2-ylamine, ethoxycarbonylisothiocyanate, and hydroxylamine hydrochloride in a manner analogous to Steps 2a-b. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.24 (s, 1H), 8.08 (s, 1H), 6.62 (bs, 2H). MS=282.9 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:40]=3[N:39]=[CH:38][CH:37]=[CH:36]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Nc1cccc2cccnc12
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc4cccnc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 100 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.10 g, 0.24 mmol) obtained in Example 19, step 4 and 8-aminoquinoline (0.069 g, 0.48 mmol), the title compound (0.125 g, 99%) was obtained.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]([O-:32])(=[O:33])[CH2:28][CH2:29][C:30]([O-:6])=[O:31]
Reactant: O=C1CCC(=O)O1
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of Hydrocortisone (3.65 g, 10 mmol) in acetonitrile (450 ml), succinic anhydride (1.65 g, 15 mmol) and DIEA (1.7 ml, 10 mmol) were added and the reaction mixture stirred at room temperature for 36 h. HPLC analysis of the reaction mixture showed 93% of the title compound. The solvent was evaporated and the residue redissolved in ethyl acetate and washed with water. The ethyl acetate phase was evaporated under reduced pressure and the residue triturated in diethyl ether to obtain 4.4 g of white powder in 95% yield. RtI 5.94′.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)#[CH:13]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:13][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(F)cc1
Product: Cc1cc2ncc(C#Cc3ccc(F)cc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=252.1 (M++H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-ethynyl-4-fluoro-benzene.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([O:31]C)=[O:30])[O:17][N:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([OH:31])=[O:30])[O:17][N:16]=1
Reactant: COC(=O)Cc1ccccc1OCc1nc(CCc2nc(-c3ccccc3)oc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCc1noc(COc2ccccc2CC(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a mixture of methyl 2-[2-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetate (0.30 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.22 g, 76%) of 2-[2-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [CH2:1]([C:5]1([N:43]([CH3:45])[CH3:44])[CH2:10][CH2:9][C:8]([C:21]2[NH:22][C:23]3[C:28]([C:29]=2[CH2:30][CH2:31][N:32]2C(=O)C4C(=CC=CC=4)C2=O)=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O.NN>CO.[OH-].[Na+]>[NH2:32][CH2:31][CH2:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][C:21]=1[C:8]1([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10][C:5]([N:43]([CH3:45])[CH3:44])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]1
Reactant: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2C)(c2[nH]c3ccccc3c2CCN)CC1

Procedure:
2-(2-(2-(4-butyl-4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)cyclohexyl)-1H-indol-3-yl)ethyl)isoindolin-1,3-dione (450 mg, 0.749 mmol) and hydrazine monohydrate (2 ml, 41.2 mmol) were dissolved in methanol (20 ml) and then boiled with reflux for 45 min. For work up the batch was diluted with 1N NaOH (50 ml) and extracted with diethyl ether (3×20 ml). The combined organic phases were dried over Na2SO4 and then concentrated until dry. The product was obtained as a light beige-coloured solid with a yield of 302 mg (86%, melting point 105-112° C.). According to the NMR spectrum it was a mixture of the two possible diastereoisomers in a ratio of approx. 30:70.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH2:12][CH3:13])[C:7]=1[Cl:14])=[O:5])[CH3:2].[C:15]([C:19]1[CH:26]=[CH:25]C(CN)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:26]=[CH:25][C:2]([CH2:1][NH:3][C:4]([C:6]2[N:10]([CH3:11])[N:9]=[C:8]([CH2:12][CH3:13])[C:7]=2[Cl:14])=[O:5])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CCNC(=O)c1c(Cl)c(CC)nn1C
Reactant: CC(C)(C)c1ccc(CN)cc1
Product: CCc1nn(C)c(C(=O)NCc2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 200 °C

Procedure:
A mixture of ethyl 4-chloro-3-ethyl-1-methylpyrazole-5-carboxamide and 4-tert-butylbenzylamine is heated to 200° C. for four hours with continuous stirring. Thereafter the reaction mixture is cooled to room temperature and the reaction mixture purified by silica gel chromatography to obtain the desired product 115°-117° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][Si:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C=O)C>[N:28]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][Si:22]([CH3:26])([CH3:25])[CH2:23][CH2:24]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: C[Si]1(C)CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si]1(C)CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the Mesyl compound 18 (250 mg, 0.59 mmol) in DMF, NaN3 (78 mg, 1.20 mmol) is added and stirred at 60° C. for 2 h. Water (5 mL) is then added and extracted with DCM (2×5 mL), dried and concentrated. The crude (220 mg) is used for further steps without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].CCCCCC.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C=O)C.O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:6]2[CH3:12])=[CH:24][CH:23]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COc1cccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cccc2c1cc(C)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
4-Methoxy-2-methyl-1H-indole (805 mg, 5 mmol) was added to a mixture of 200 mg (5 mmol) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 10 mL of DMF and after stirring for 0.5 hours, 0.6 mL (5 mmol) of 4-fluorobenzyl chloride was added. The mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.1 g (84% yield) of 1-[(4-fluorophenyl)methyl]-4-methoxy-2-methyl-1H-indole, melting at 104-108° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>>[C:31]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:17]=2)=[O:14])=[CH:36][CH:35]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Cc2cccc3c(-c4ccc(C(C)=O)cc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylacetamide (E20) and 4-acetylphenylboronic acid using a similar procedure to Example 4 (20%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Cl)=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[C:5]2=[N:4][CH:3]=1.[OH-:20].[K+]>C(O)C>[C:11]([C:10]1[CH:9]=[CH:8][C:7](=[O:20])[N:6]2[C:2]([Br:1])=[CH:3][NH:4][C:5]=12)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [OH-]
Reactant: O=C(c1ccccc1)c1ccc(Cl)n2c(Br)cnc12
Agent: [K+]
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(=O)n2c(Br)c[nH]c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.2 %

Procedure:
40 mg (0.12 mmol) of 3-bromo-5chloroimidazo[1,2-a]pyridin-8-yl)(phenyl)methanone (example L) are dissolved in 5 ml of potassium hydroxide—solution (10% in water) and 5 ml of ethanol. The mixture is stirred for 24 h at rt. The solvent is evaporated under vacuum and water is added to the crude. The solution is extracted for with ethyl acetate. The collected organic phases are reextracted with brine solution and dried over sodium sulfate. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-Column, eluent: acetonitrilewater-gradient) to yield 1.6 mg (4.2% of th.) 8-Benzoyl-3-bromoimidazo[1,2-a]pyridin-5(1H)-one.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH2:19][O-:20].[Na+]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:20][CH2:19][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
5 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile in 60 ml of absolute alcohol are heated to reflux temperature for 1 hour in the presence of 30 mg of sodium ethylate. After distilling off the alcohol the residue is treated with water and the mixture is extracted three times with methylene chloride. The combined extracts are washed with water, dried over anhydrous sodium sulphate and evaporated, and the residue is distilled in a bulb-tube oven at 230°-250° C./0.1 mmHg. There is obtained ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a clear resin which becomes solid; m.p. 68°-71° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:27](O)=[O:28]>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:27]=[O:28])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CCCCCCCCc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of n-octylbenzene (1.2 g; 6.3 mmol) hexamethylenetetramine (0.97 g; 6.93 mmol) in trifluoroacetic acid (TFA) was refluxed for 4 h, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was neutralized with 5% NaHCO3 and extracted with diethyl ether (Et2O) (3×5 ml). The combined organic phase was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane) to give the title compound (0.4 g; 29%) as a colourless oil and starting n-octylbenzene (0.8 g; 67%). 1H-NMR (CDCl3) 9.96 (s, 1H); 7.77 (d, 2H, J=8.1 Hz); 7.31 (d, 2H, J=8.1 Hz); 2.67 (t, 2H, J=7.9 Hz); 1.6 (m, 2H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.9 Hz);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7]2.C1C(N=NC2C(=O)N(C3C=C[C:41]([S:44]([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C(Cl)(Cl)=S.C>O.Cl>[N:1]([C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:7]2)=[C:41]=[S:44]
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Reactant: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: S=C(Cl)Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1cc(N=C=S)c2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Reaction time: 2 h

Procedure:
To a solution of 32.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt in 350 ml of water and 7.0 ml of concentrated hydrochloric acid was added 10.0 g of thiophosgene. The mixture was stirred 21/2 hours, treated with charcoal and filtered through diatomaceous earth. The filtrate was neutralized with 46 ml of 5N sodium hydroxide, chilled and the solid was collected and recrystallized from 40 ml of water by heating and then chilling in an ice bath. This solid was washed with ice water, acetone then ether and dried, giving 11.2 g of 8-isothiocyanato-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24]OS(C)(=O)=O)[O:21][C:20]4=[O:30])=[CH:15][C:14]=3[F:31])=[CH:9][N:8]=2)=[N:3]1.Cl.[CH3:33][NH:34][CH3:35]>CN(C)C=O>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@@H:22]([CH2:24][N:34]([CH3:35])[CH3:33])[O:21][C:20]4=[O:30])=[CH:15][C:14]=3[F:31])=[CH:9][N:8]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)cn2)n1
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C[C@@H]1CN(c2ccc(-c3ccc(-c4nnn(C)n4)nc3)c(F)c2)C(=O)O1
Temperature: 60 °C
Reaction time: 30 h
Yield: 79 %

Procedure:
In 5 ml of dimethylformamid was dissolved 100 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 30 mg of dimethylamine hydrochloride at room temperature. The solution was stirred for 30 hours at the temperature of 60° C. And then the solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The residue, prepared by dehydrating, filtering and concentrating the organic layer, was purified by column chromatography to provide the title compound 70 mg. Yield 76%.
Reaction SMILES: C([N:8]1[CH:17]2[CH:12]([CH:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH2:16]2)[N:11]([C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>C1COCC1.O.[Pd]>[Cl:32][C:27]1[CH:26]=[C:25]([CH2:24][C:23]([N:11]2[CH:12]3[CH:17]([CH2:16][CH2:15][CH2:14][CH:13]3[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[NH:8][CH2:9][CH2:10]2)=[O:33])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)C2CCCC(N3CCCC3)C21
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[(4aRS,8SR,8aRS)-4-Benzyl-8-(pyrrolidin-1-yl)perhydroquinoxalin-1-yl]-2-(3,4-dichlorophenyl)ethan-1-one (244 mg, 0.50 mmol) was dissolved in THF/H2O (1:1, 50 ml), and conc. HCl (5 ml) and palladium-on-carbon (Pd/C) (Merck) (98.4 mg) were added. The mixture was stirred under 1 bar of H2 at room temperature for 30 minutes. The catalyst was filtered off and THF was evaporated off in vacuo. The aqueous phase was brought to pH 8 with NaOH (2 N) and extracted by shaking five times with CH2Cl2. The combined organic phases were dried over Na2SO4 and evaporated. The yellowish residue was purified by column chromatography over silica gel 60 (40-63 μm, (Merck) column Ø 3 cm, CH2Cl2/MeOH/NH3 9:1:0.1, l=17 cm, V=10 ml) and gave a yellow resin.