Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:14][CH2:13][CH:12]([N:15]=[N+]=[N-])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[C:1]([O:9][CH:10]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC1CCC(OC(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: NC1CCC(OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of 3-azidocyclopentyl benzoate (411 mg) and 10% palladium on activated carbon (41.1 mg) in methanol (15 mL) was stirred under hydrogen atmosphere (4 atm) for 2 hours at ambient temperature. After removal of the catalyst, the filtrate was evaporated in vacuo to give 3-aminocyclopentyl benzoate as a pale yellow oil (354 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@@H:9]([NH:24][C:25](=[O:42])[C@@H:26]([NH:34]C(OC(C)(C)C)=O)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]1=[O:43])(=[O:3])[CH3:2].C(OCCN1C2C=CC=CC=2C(C2C=CC=CC=2)=N[C@H](NC(=O)[C@@H](NC(OC(C)(C)C)=O)CC2C=CC=CC=2)C1=O)(=O)C.Cl>C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@@H:9]([NH:24][C:25](=[O:42])[C@@H:26]([NH2:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]1=[O:43])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN1C(=O)[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(c2ccccc2)c2ccccc21
Agent: CC(=O)OCCN1C(=O)[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCCN1C(=O)[C@H](NC(=O)[C@@H](N)Cc2ccccc2)N=C(c2ccccc2)c2ccccc21
Yield: 98.3 %

Procedure:
To a solution of a mixture (0.7 g) of (3R)-1-(2-acetoxyethyl)-1,3-dihydro-5-phenyl-3- [((2S )-2-tertbutoxycarbonylamino-3-phenylpropanoyl)amino ] -2H-1,4-benzodiazepine-2-one and (3S )-1-(2-acetoxyethyl )-1,3-dihydro-5-phenyl -3-[((2S )-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-2H-1,4-benzodiazepine-2-one in ethyl acetate (20 ml) was introduced hydrogen chloride gas under cooling in an ice-bath with stirring. After the solution was saturated with hydrogen chloride, the mixture was stirred for 30 minutes under the same temperature and for 1 hour at ambient temperature. After removal of the hydrogen chloride by bubbling dried nitrogen gas, the mixture was evaporated under reduced pressure. To the residue was added water and the mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate twice and the extract was washed with water and dried over magnesium sulfate. Removal of the solvent afforded a mixture (0.57 g) of (3R)-1-(2-acetoxyethyl)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-2H -1,4-benzodiazepine-2-one and (3S)-1-(2-acetoxyethyl)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:14]1)=[O:12])[CH3:10])=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH2:8][C@H:9]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]1)=[O:12])[CH3:10]
Reactant: COC(=O)COC1CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)COC1CCN(C(=O)[C@H](C)N)CC1

Procedure:
Prepared from methyl N-(tert-butyloxycarbonyl-L-alanyl)-4-piperidinyloxyacetate and trifluoroacetic acid in methylene chloride analogously to Example 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10](C)=[N:9]1.N[CH2:25][C@@H]1OC(=O)N(C2C=CC(N3C=C(C)N=N3)=C(F)C=2)C1.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][N:11]([CH3:25])[CH:10]=[N:9]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CN)OC3=O)cc2F)nn1
Reactant: Cc1ncn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)n1
Solvent: ClCCl
Solvent: CO
Product: CN1C=NN(c2ccc(N3CC(CN)OC3=O)cc2F)C1

Procedure:
3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-(azidomethyl)oxazolidin-2-one (Intermediate 24) (1.8 g, 5.67 mmol) was hydrogenated as described for Intermediate 16. Chromatography on silica gel with 3-7% methanol in dichloromethane gave the title compound (1.28 g).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=3)[C:10](=O)[CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1([CH2:6][CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Nc1ccc(N2CCCN(CCC3CCCC3)CC2=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CS(=O)(=O)Nc1ccc(N2CCCN(CCC3CCCC3)CC2)cc1

Procedure:
In a manner similar to Example 1 react N-[4-[4-(2-[cyclopentyl)ethyl]hexahydro-2-oxo-1H-1,4-diazepin-1-yl]phenyl]methanesulfonamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:21]#[C:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:15][CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CCO.[Rh]>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])=[CH:15][CH:16]=2)[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc2ccc(C#CC(C)(C)O)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Agent: [Rh]
Solvent: CCO
Product: Cc1cc2ccc(CCC(C)(C)O)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (8 mg, 0.017 mmol) in EtOH (1 mL) was added rhodium on alumina (2 mg). The reaction was flushed with hydrogen gas and then stirred under and hydrogen atmosphere for 1 h. The reaction was filtered and concentrated in vacuo to give 7 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.68 (d, J=8 Hz, 1H), 7.63 (m, 1H), 7.61 (s, 1H), 7.53 (m, 2H), 7.30 (m, 2H), 7.05 (s, 1H), 5.12 (s, 1H), 2.65 (m, 2H), 2.59 (s, 3H), 1.66 (m, 2H), 1.19 (s, 6H), 0.96 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 4.0 min run): tR (min)=3.52.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OS([O-])=O.[Na+].Cl.Cl.[NH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:24]([NH2:26])=[NH:25].C(O)C>O>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]2[NH:30][C:29]3[CH:28]=[CH:27][C:23]([C:24](=[NH:25])[NH2:26])=[CH:22][C:21]=3[N:20]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: N=C(N)c1ccc(N)c(N)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(-c2nc3cc(C(=N)N)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-tert-butylbenzaldehyde (0.4000 g, 0.00247 mol) was added 3 mL of 40% NaHSO3 (aq). The mixture was stirred for 2 h at 25° C. 3,4-Diaminobenzamidine dihydrochloride (0.56 g, 0.0025 mol) and ethanol (8 mL) were added. The mixture was refluxed for 3 h. The reaction was then poured into water. The precipitate filtered and recrystallized from 2N HCl to afford 1H-benzimidzole-5-carboximidamide, 2-[4-(1,1-dimethylethyl)phenyl]- (400 mg, 44%) as a white solid: 1H NMR (DMSO-d6) δ9.47 (bs, 2 NH), 9.15 (bs, 2 NH), 8.30 (d, 2 arom-H, J=8 Hz), 8.21 (s, 1 arom-H), 7.88 (d, 1 arom-H, J=8 Hz), 7.73 (d, 1 arom-H, J=9 Hz), 7.68 (d, 2 arom-H, J=8 Hz), 1.35 (s, 9 tert-butyl-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:18](=[CH:24]N(C)C)[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=O)[CH3:16]>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[CH:24]=[N:14][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[C:15]=1[CH3:16])=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Yield: 91.8 %

Procedure:
By the method of Example 5, Step A, 101.3 g (0.4134 mole) of 2,6-dichloro-4-trifluoromethylphenylhydrazine and 76.8 g (0.415 mole) of ethyl 2-acetyl-3-dimethylaminoacrylate were reacted in 1944 mL of ethanol, yielding 139.4 g of 4-ethoxycarbonyl-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole as a viscous oil. A 4 g sample of this oil was removed and allowed to crystallize. The nmr spectrum of this waxy solid was consistent with the proposed structure.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:14])=[C:10]([NH2:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2].CO.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[O-2].[O-2].[Mn+4].C(O)(=O)C>[C:1]([N:4]1[C:12]2=[CH:11][C:10]3[NH:13][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:14][C:9]=3[CH:8]=[C:7]2[C:6]([CH3:16])([CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N1CC(C)(C)c2cc(N)c(N)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1CC(C)(C)c2cc3nc(-c4ccccc4)[nH]c3cc21

Procedure:
A mixture of 2.2 g. (10 mmole) 1-acetyl-5,6-diamino-3,3-dimethylindoline, 200 ml. methanol, 5.2 ml. acetic acid, 1.0 ml. benzaldehyde and 50 mg. manganese dioxide is stirred for 3 hours at ambient temperature while passing in air. The reaction mixture is then filtered, the filtrate evaporated and the residue chromatographed on silica gel. After evaporation of the appropriate fractions and trituration with diethyl ether, there is obtained 0.8 g. (26% of theory) of the title compound; m.p. 225°-227° C.
Reaction SMILES: [CH2:1]([C:15]1[C:16]([CH2:23][OH:24])=[C:17]([OH:22])[C:18]([CH3:21])=[N:19][CH:20]=1)[S:2][S:3][CH2:4][C:5]1[C:6]([CH2:13][OH:14])=[C:7]([OH:12])[C:8]([CH3:11])=[N:9][CH:10]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CCOCC>[CH2:4]([C:5]1[CH:10]=[N:9][C:8]([CH3:11])=[C:7]2[O:12][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:14][CH2:13][C:6]=12)[S:3][S:2][CH2:1][C:15]1[CH:20]=[N:19][C:18]([CH3:21])=[C:17]2[O:22][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:24][CH2:23][C:16]=12
Reactant: O=Cc1ccccc1
Reactant: Cc1ncc(CSSCc2cnc(C)c(O)c2CO)c(CO)c1O
Agent: Cl
Solvent: CCOCC
Product: Cc1ncc(CSSCc2cnc(C)c3c2COC(c2ccccc2)O3)c2c1OC(c1ccccc1)OC2
Reaction time: 4 h

Procedure:
A mixture of 0.01 moles of 5,5'-(dithiodimethylene) bis[3-hydroxy-4-hydroxymethyl-2-methylpyridine] and 100 ml. of benzaldehyde was saturated with hydrogen chloride gas at 0°-5° and then stirred at this temperature for 4 hours. At this time 800 ml. of ether were added and the resulting precipitate was separated by filtration. This solid was then added to a well stirred mixture of 200 ml. chloroform and 200 ml. of water containing 20 gm. of sodium carbonate. After 15 minutes the chloroform layer was removed, dried, and concentrated to give an oil which gradually solidified. This solid was filtered with the aid of a small amount of ether to give 5,5'-(dithiodimethylene)bis[8-methyl-2-phenyl-4H-m-dioxino[4,5-c]pyridine].
Reaction SMILES: C([O-])(=O)C.[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][N+:20]([CH2:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:6].[BH4-].[Na+]>CO.CCOC(C)=O>[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:6]
Reactant: CCC[n+]1ccc(-c2ccc([N+](=O)[O-])c(OCC)c2)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OCC)c2)CC1
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To 4-[3-(ethyloxy)-4-nitrophenyl]-1-propylpyridinium acetate (0.84 g, 2.42 mmol) in 25 mL of MeOH at 0° C. was added, NaBH4 (0.275 g, 7.28 mmol) over 1 h. The mixture was allowed to come to rt over 2 h. The solvent was reduced to approximately 5 mL and then diluted with EtOAc, washed with conc. NaHCSO3, dried (Na2SO4), filtered, rotovaped down, and purified by flash chromatography to give the title compound of step D (0.536 g, 1.85 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (d, J=8.61 Hz, 1H), 7.23 (d, J=1.46 Hz, 1H), 7.11 (dd, J=8.42, 1.65 Hz, 1H), 6.37 (t, J=3.57 Hz, 1H), 4.23 (q, J=6.96 Hz, 2H), 3.06 (d, J=3.11 Hz, 2H), 2.58 (t, J=5.59 Hz, 2H), 2.44-2.50 (m, 2H), 2.29-2.35 (m, 2H), 1.41-1.51 (m, J=7.36, 7.36, 7.36, 7.36, 7.36 Hz, 2H), 1.31 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.33 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:7]=[C:6]([C:17]2[C:18]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1I
Reactant: OB(O)c1cccc2ccccc12
Product: Brc1cccc(-c2cccc3ccccc23)c1

Procedure:
1-(3-Bromophenyl)naphthalene was synthesized by the same method, except that in Synthetic Example 1, 2-bromoiodobenzene was used in place of 4-bromoiodobenzene and that 1-naphthaleneboronic acid was used in place of 2-naphthaleneboronic acid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.[C:10]([N:13]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17]C2N=C(Cl)C(F)=CC=2C1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH2:8]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Reactant: OCc1ccncc1I
Product: CC(=O)N1Cc2ccncc2C=Cc2ccccc21

Procedure:
Compound 24C was prepared from 24A and bb in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=1.383 min; LCMS Found: (M+H)+=251.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[N:15]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>O1CCCC1.C(O)C>[C:20]([NH:19][C:16]([C:14]1[N:15]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:23])=[O:3])=[CH:10][CH:9]=2)[S:12][CH:13]=1)([CH3:18])[CH3:17])(=[O:22])[CH3:21]
Reactant: CCOC(=O)c1ccc(-c2nc(C(C)(C)NC(C)=O)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)NC(C)(C)c1csc(-c2ccc(C(=O)O)cc2)n1
Yield: 89.3 %

Procedure:
4-[4-(1-Acetylamino-1-methyl-ethyl)-thiazol-2-yl]-benzoic acid ethyl ester (0.13 g, 0.39 mmol) is dissolved in 2 mL tetrahydrofuran and 2 mL ethanol. 2N sodium hydroxide (1.17 mmol, 0.587 mL) is added and the mixture is heated to reflux for 1 hour. The reaction is concentrated to dryness and the resulting residue is dissolved in 95:5 dichloromethane/isopropanol layered with 0.1N HCl. The organics are separated and dried over sodium sulfate, filtered, and concentrated to give 0.106 g of the pure titled compound. MS (m/e) 303.2 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16](I)[N:11]3[N:10]=2)=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16]([C:25]4[CH:26]=[CH:27][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:23][CH:24]=4)[N:11]3[N:10]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Nc2nn3c(I)cnc3s2)cc1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2cnc3sc(Nc4ccc(F)cc4)nn23)cc1
Temperature: 140 °C
Yield: 15.1 %

Procedure:
(4-Fluoro-phenyl)-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-amine (0.065 g, 0.18 mmol) was suspended in 1,4-dioxane (1 mL) at room temperature, and Argon was bubbled into the mixture while dichlorobis(triphenylphosphine)-palladium(II) (13 mg, 0.018 mmol), 4-acetamidophenylboronic acid (37 mg, 0.21 mmol), cesium carbonate (118 mg, 0.36 mmol) and water (1 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 30 minutes. On cooling, the mixture was diluted with dichloromethane (5 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.4:9.6 to 1.5:8.5). The product obtained was treated with diethylether (7 mL) and filtered to give N-{4-[2-(4-fluoro-phenylamino)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenyl}-acetamide as an off-white solid (10 mg, 15% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[O:17])=[C:11]([OH:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33](Br)Br.C(O)=O>CN1C(=O)N(C)CC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([N:15]2[C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[O:30][CH2:33]2)=[O:17])=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(OCc2ccccc2)cc1O
Reactant: BrCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O=CO
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(OCc3ccccc3)ccc21
Reaction time: 0.25 h

Procedure:
To a solution of 1.4 g (3.2 mMol) of 1-(4-benzyloxy-2-hydroxy-phenyl)-3-(4-chloro-3-trifluoromethyl-phenyl)-urea in 420 ml DMEU, 700 mg NaH (55% in oil; 16 mMol) are given. After 15 min, 23 ml of CH2Br2 are added and stirring is continued for 6 h. Then 1 ml of formic acid is added and the resulting mixture is evaporated in HV. The residue is dissolved in EtOAc and water. The separated aq. phase is extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/CH2Cl2 1:1→CH2Cl2) gives the title compound: m.p.: 135-136° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:32]=[CH:31][C:19]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)=[O:21])=[CH:18][CH:17]=2)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:30][N:28]([CH3:29])[CH:25]1[CH2:26][CH2:27][N:22]([C:20](=[O:21])[C:19]2[CH:31]=[CH:32][C:16]([N:14]3[CH:15]=[C:11]([C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([CH:3]=[C:4]([CH3:8])[CH3:5])[CH:3]=5)[NH:7][N:6]=4)[N:12]=[N:13]3)=[CH:17][CH:18]=2)[CH2:23][CH2:24]1
Reactant: CN(C)C1CCN(C(=O)c2ccc(-n3cc(-c4n[nH]c5ccc(Br)cc45)nn3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)=Cc1ccc2[nH]nc(-c3cn(-c4ccc(C(=O)N5CCC(N(C)C)CC5)cc4)nn3)c2c1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
A mixture of 1-{4-[4-(5-bromo-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-N,N-dimethylpiperidin-4-amine (160 mg; 0.32 mmol; 1.0 eq.), 1-{4-[4-(5-bromo-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}-N,N-dimethylpiperidin-4-amine (160 mg; 0.32 mmol; 1.0 eq.), PdCl2dppf (24 mg; 0.03 mmol; 0.1 eq.) and potassium carbonate (224 mg; 1.62 mmol; 5.0 eq.) in dioxane (1 mL) and water (1 mL) was heated at 80° C. O/N in a sealed tube. The reaction mixture was then filtered through a celite pad and filtrate was extracted twice with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient form 90:10 to 50:50) gave the title compound as a brown powder (68 mg, 45%).
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:21]=2)=[CH:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH:29]1([O:28][C:22]2[CH:21]=[C:20]([C:12]3[NH:11][C:10]([CH2:9][OH:8])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=3)[CH:25]=[CH:24][C:23]=2[O:26][CH3:27])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)c(OC3CCCC3)c2)[nH]c1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OC)c(OC3CCCC3)c2)[nH]c1CO
Temperature: 30 °C
Reaction time: 1.25 h
Yield: 43.3 %

Procedure:
To 280 ml of ethanol solution containing 3.15 g (7.0 mmol) of ethyl 2-benzyloxymethyl-5-(3-cyclopentoxy-4-methoxyphenyl)-1H-pyrrol-3-carboxylate obtained in Reference example 47-(c) was added 600 mg of 10% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 11 hours. Then, the mixture was stirred at 30° C. for 1.25 hours, and further at 40° C. for 13 hours. After completion of the reaction, the reaction suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.09 g of the title compound as a yellowish oil. (Yield: 43%)
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=2)[CH2:3][CH2:2]1.[CH:17]1(C2N=C(SC)N=C(C(O)=O)C=2)CC1.OOS([O-])=O.[K+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].OS([O-])(=O)=O.[K+].CSC1N=CC=CN=1>O.C(#N)C>[CH:1]1([C:4]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:11])=[O:12])[N:7]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CSc1nc(C(=O)O)cc(C2CC2)n1
Reactant: CS(=O)(=O)c1nc(C(=O)O)cc(C2CC2)n1
Agent: CSc1ncccn1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(C2CC2)nc(S(C)(=O)=O)n1
Temperature: 65 °C

Procedure:
6-cyclopropyl-2-(methylsulfonyl)pyrimidine-4-carboxylic acid (I-20A). Into a 40 mL vessel was added 6-cyclopropyl-2-(methylthio)pyrimidine-4-carboxylic acid_(commerically available, Enamine Ltd, catalog number EN300-422464, 250 mg, 1.19 mmol) and acetonitrile (12.5 mL). This resulting solution was then added dropwise at RT over 5 min. to a separate 40 mL reaction vessel that was charged with a rapidly stirred suspension of Oxone™ (using Aldrich supplied Oxone which is a multicomponent triple salt mixture containing potassium monopersulfate, 2 KHSOs5.KHSO4.K2SO4, 2.50 g, 4.10 mmol) and water (15 mL). Upon complete addition of the methyl thiopyrimidine, the resulting suspension was heated to 65° C. for 20 min. and subsequently cooled to RT. The resulting yellow suspension was extracted with ethyl acetate (4×100 mL) and the organic extracts were dried over magnesium sulfate, filtered and concentrated to furnish the methyl sulfonyl pyrimidine as a residue that was used directly in the next step without isolation. MS m/z 243.1 (M+1).