Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.C(O[CH:12]=[C:13]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])C>C1(C)C=CC=CC=1>[C:17]1([S:14]([C:13]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:12][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:12]=[C:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:15])=[O:16])[S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[N:3]=2)(=[O:15])=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: Nc1cccc(N)n1
Solvent: Cc1ccccc1
Product: O=S(=O)(C(=CNc1cccc(NC=C(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)n1)S(=O)(=O)c1ccccc1)c1ccccc1
Yield: 22.7 %

Procedure:
A stirred mixture of 2,6-diaminopyridine (0.3 g) and 2-ethoxy-1,1-bis(phenylsulphonyl)ethene (2.1 g) in toluene (50 ml) was heated at reflux for 2 hours. The mixture was cooled, and concentrated in vacuo, and the resulting solid was subjected to medium pressure chromatography on silica gel, eluting with acetone, to give 2,6-bis[2,2-bis(phenylsulphonyl)ethen-1-ylamino]pyridine (0.45 g), in the form of a white powder, m.p. 299°-300° C.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1>C(Cl)Cl>[CH2:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Reactant: CCCN=C=O
Solvent: ClCCl
Product: CCCNC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Propylisocyanate (13 μl, 137 μmol) was added to a solution of 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 15.8 mg, 691 mol) in CH2Cl2 (0.7 ml). After stirring 18 h at rt, the solvent was removed to afford the title compound: RT=2.72 min; m/z (ES+)=316.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH2:7][CH2:6]2.[C:27](Cl)(=[O:29])[CH3:28].C(OCC)(=O)C>N1C=CC=CC=1>[C:27]([N:22]1[C:23]2[C:19](=[C:18]([NH:17][C:15]([NH:14][CH:8]3[C:9]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)[CH2:6][CH2:7]3)=[O:16])[CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:21]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(NC(=O)Nc1cccc3[nH]ncc13)CC2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)C(NC(=O)Nc1cccc3c1cnn3C(C)=O)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
To the solution of 1-(5,6-dimethoxy-indan-1-yl)-3-(1H-indazol-4-yl)-urea (0.1 g, 0.28 mmol) in pyridine (2 mL) was added acetyl chloride (0.5 mL) and mixture stirred for 15 hours at ambient temperature. The mixture was suspended with ethyl acetate and filtered. The precipitate was triturated with ether twice and dried to obtain 42 mg (38%) of desired product as a yellow solid. NMR (DMSO-d6): 8.98 (s, 1H), 8.72 (s, 1H), 7.60 (d, J 7.5 Hz, 1H), 7.32-7.18 (m, 2H), 6.90 (d, J 8Hz, 2H), 6.53 (d, J 8 Hz, 1H), 5.16 (m, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.00-2.70 (m, 5H), 2.43 (m, 1H), 1.82 (m, 1H). MS (DCI): 395 (M+1). Elemental: Calculated for C18H18N4O2.0.2 H2O: C 63.37, H 5.67, N 14.08; Found: C 63.07, H 5.49, N 13.94.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Clc1ccccc1C(Cl)Cn1ccnc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
6.4 g of methyl 4-mercaptobenzoate were dissolved in 45 ml of dry dimethylformamide, and 1.7 g of a 55% w/w suspension of sodium hydride in mineral oil was added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 30 minutes, after which a solution of 9.2 g of 1-[2-chloro-2-(2-chlorophenyl)ethyl]imidazole in 45 ml of dry dimethylformamide was added to the resulting solution, and the reaction mixture was heated at 50° C. for 6.5 hours. At the end of this time, the resulting solution was treated and purified in a similar manner to that described in Example 1, to give 8.08 g of the title compound as an oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:10]2)(=O)=O.[CH3:31][N:32](C=O)C>C(OCC)(=O)C.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.[C-]#N.[Zn+2].[C-]#N>[C:31]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:11][CH2:10]2)#[N:32]
Reactant: CCOC(=O)C1c2ccc(OS(=O)(=O)C(F)(F)F)cc2CCN1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1c2ccc(C#N)cc2CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A mixture of 1-ethyl 2-tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (7.44 g, 16.41 mmol), Pd(PPh3)4 (0.948 g, 0.82 mmol), zinc cyanide (2.119 g, 18.05 mmol) and DMF (100 mL) was stirred overnight at 100° C. The reaction mixture was diluted with ethyl acetate, and filtered. The filtrate was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→60% ethyl acetate/hexane) to give 1-ethyl 2-tert-butyl 6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (4.92 g, 14.89 mmol, 91%) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13](Br)[CH2:14][CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:14][CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cccc3c2C(CCC3Br)C1c1ccccc1
Reactant: C1CCNC1
Product: CC(=O)N1c2cccc3c2C(CCC3N2CCCC2)C1c1ccccc1
Yield: 76 %

Procedure:
The compound (500 mg) obtained in Example 187 and pyrrolidine (0.24 ml) were subjected to amination according to the procedure of Example 134 to yield 370 mg (76%) of the titled compound as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH3:22])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:26][CH2:25]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH3:22])=[CH:16][CH:15]=3)=[N:4][N:3]=[C:2]2[NH:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)[CH2:28][CH2:29]2)=[CH:7][CH:8]=1
Reactant: COCc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COCc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(OC)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(4-methoxymethylphenyl)phthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:4][C:3]=1[CH:15]=O.[N:17]1[C:26]2[CH:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:15][C:3]1[N:4]=[CH:5][N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[C:2]=1[CH2:1][N:27]([CH:25]1[C:26]2[N:17]=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:22][CH2:23][CH2:24]1)[CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[C:33](=[O:42])[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]1=[O:41]
Reactant: Cc1c(C=O)ncn1COCC[Si](C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ncn(COCC[Si](C)(C)C)c1CN(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21

Procedure:
Using General Procedure B: Reaction of 5-Methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbaldehyde from above with 2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione and NaBH(OAc)3 gave 2-{4-[[5-Methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a white foam. 1H NMR (CDCl3) 6-0.04 (s, 9H), 0.87 (t, 2H, J=8.1 Hz), 1.38-1.53 (m, 2H), 1.54-1.71 (m, 3H), 1.90-2.11 (m, 3H), 2.22 (s, 3H), 2.50-2.86 (m, 4H), 3.43 (t, 2H, J=8.3 Hz), 3.52-3.65 (m, 3H), 3.75 (d, 1H, J=13.1 Hz), 4.03-4.13 (m, 1H), 5.15 (s, 2H), 7.00 (dd, 1H, J=7.6, 4.7 Hz), 7.30 (d, 1H, J=6.2 Hz), 7.40 (s, 1H), 7.66-7.72 (m, 2H), 7.77-7.85 (m, 2H), 8.45 (dd, 1H, J=4.4, 1.5 Hz).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:3]=1.CCN(CC)CC.[NH2:30][OH:31].Cl>CCO>[OH:31][N:30]=[C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]=[C:2]2[I:1])[NH2:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C#N)ccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(N)=NO)ccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
To a suspension of 3-iodo-1-tosyl-1H-indole-5-carbonitrile (1 g, 2.37 mmol) in EtOH (10 mL) was added Et3N (1.65 mL, 11.87 mmol) followed by NH2OH.HCl (410 mg, 5.93 mmol) and the reaction was stirred for 48 h at RT. The solvent was removed in vacuo and the residue was treated with H2O (10 mL) and extracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was further triturated with n-pentane to give N′-hydroxy-3-iodo-1-tosyl-1H-indole-5-carboximidamide (950 mg, 88.7%) as an off brown solid. MS (ESI, pos. ion) m/z: 455.8; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.8 Hz, 1H), 7.84-7.73 (m, 4H), 7.68 (d, J=8.4 Hz, 1H), 7.63-7.61 (m, 1H), 7.31-7.24 (m, 1H), 4.92 (brs, 2H), 3.14-3.09 (m, 1H), 2.36 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:28]=4)[NH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CCC(=O)Nc1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Nc1ccc2[nH]cc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-propionamido-1H-indole-1-carboxylate (200 mg, 0.35 mmol) in DCM (2 mL) was treated with TFA (2 mL) and stirred at RT for 12 h. The reaction mixture was quenched with water and neutralized with K2CO3. The resulting precipitate was filtered, washed with water and dried to obtain the crude product. The crude product was purified by prep HPLC (column: Zorbax Eclipse XDBC Prep C18 5 μm 21.2*150 mm; flow rate: 15.0 mL/min; mobile phase: A: 0.1% TFA in water. B: ACN+MeOH (1:1); gradient: % B, 10% to 50%) to N-(3-(6-(4-aminopiperidin-1-yl)pyrazin-2-yl)-1H-indol-5-yl)propionamide (234) (50 mg, 39%). MS (ESI, pos. ion) m/z: 413.2 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH:8]=[C:7]([NH2:17])[CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:17][C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH:8]=1
Reactant: CCOC(=O)c1cc(N)cc(-c2nnnn2C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nnnc1-c1cc(N)cc(CO)c1
Reaction time: 3 h
Yield: 33.7 %

Procedure:
To a solution of 3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid ethyl ester (250 mg) in THF (5 ml) at 0° C. was added pre-cooled 1M LiAlH4 solution in THF (2 ml) dropwise. This was stirred for 3 h. The reaction mixture was poured onto ice-water and extracted into EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash chromatography (100:0 to 95:5 gradient DCM:MeOH) afforded the title compound (70 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Reactant: C1CCNC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1I

Procedure:
A solution of N-(3-iodo-4-methylphenyl)-2-chloro-isonicotinamide (Intermediate 20)(7.00 g, 18.8 mmol) in pyrrolidine (20 ml) was heated at 80° C. under an atmosphere of nitrogen for 16 hours. Excess pyrrolidine was removed in vacuo and the residue was titurated with dietheyl ether (20 ml). The resulting solid was collected by filtration and dried in vacuo to give N-(3-iodo-4-methylphenyl)-2-pyrrolidin-1-yl-isonicotinamide as a pale yellow solid (7.73 g, 18 mmol). LCMS: retention time 2.77 min MH+ 408. NMR: δH [2H6]-DMSO 10.29 (1H, s), 8.29 (1H, d), 8.20 (1H, d), 7.71 (1H, dd), 7.72 (1H, dd), 6.97 (1H, brd), 6.88 (1H, b), 3.45 (2H, apparent t), 3.09 (2H, m), 2.35 (3H, s), 1.98 (2H, m), 1.82 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]#C)[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[CH3:15]N(C)C=O>>[CH3:1][N:2]1[C:7]2[CH:15]=[C:9]([CH3:10])[NH:8][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: C#CCNc1cn(C)c(=O)n(C)c1=O
Reactant: CN(C)C=O
Product: Cc1cc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
A solution of Step 2 intermediate (500 mg, 2.587 mmol) in dry N,N-dimethylformamide (20 mL) was refluxed for 40 h under nitrogen atmosphere. The excess of solvent was evaporated and the residue obtained was purified by silica gel column chromatography by using 5% methanol in chloroform to obtain 200 mg of the product as a yellow solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.26 (s, 3H), 3.21 (s, 3H), 3.33 (s, 3H), 5.91 (s, 1H), 11.84 (br s, 1H); ESI-MS (m/z) 194.28 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1[C:9]([OH:10])=[N:8][S:7][N:6]=1.Br[CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1[C:9]([O:10][CH:30]([C:31]([O:33][CH3:34])=[O:32])[CH3:35])=[N:8][S:7][N:6]=1
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nsnc3O)c(Cl)cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1nsnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
200 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-1,2,5-thiadiazole and 150 mg of methyl 2-bromopropionate were dissolved in 10 ml of N,N-dimethylformamide, to this was added 100 mg of potassium carbonate, and the mixture was stirred for 3 hours at room temperature. This reaction solution was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, then, saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-[1-(methoxycarbonyl)ethoxyl]-1,2,5-thiadiazole [present compound 10-2].
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.Cl[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=2)[CH:10]=[C:9]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:8]=1>>[CH3:23][O:22][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]([O:5][CH:3]1[CH2:4][O:1][CH2:2]1)=[N:8][C:9]([NH:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1)=[CH:10]2
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Reactant: OC1COC1
Product: COCCOc1cc2c(OC3COC3)nc(Nc3cc(C)[nH]n3)cc2cc1OC

Procedure:
Similar procedure as described in example 400 was used, starting from oxetan-3-ol and [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine to give [6-Methoxy-7-(2-methoxy-ethoxy)-1-(oxetan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 401 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][S-:13].[Na+].O>CN(C)C=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([S:13][CH3:12])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: COc1ccc(F)c(C#N)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(SC)c(C#N)c1
Yield: 70 %

Procedure:
(Step 1) A mixture of 2-fluoro-5-methoxybenzonitrile (10 g) and sodium methanethiolate (5.1 g) was stirred in N,N-dimethylformamide (20 ml) at 60° C. for 3 hr. The reaction solution was treated with water, and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give 5-methoxy-2-(methylsulfanyl)benzonitrile (8.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-ethylamine, (0.055 g, 0.21 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.046 g, 0.30 mmol) and DIPEA (0.07 mL, 0.38 mmol) in IPA (1.5 mL) was stirred at 80° C. in a sealed tube for 16 h. After cooling, the reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) to give 418 as a white solid (0.060 g, 75%). LCMS (Method K): RT 2.94 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.12 (1H, s), 7.96 (1H, s), 7.70-7.60 (3H, m), 7.25 (2H, s), 7.09 (1H, m), 6.96 (1H, m), 5.46 (1H, m), 3.88 (3H, s), 1.51 (3H, d, J=6.85 Hz)
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:42]([CH3:43])=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:54][NH2:55]>C(O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:35]([CH3:44])=[CH:36][C:37]([C:38]([NH:54][NH2:55])=[O:40])=[CH:41][C:42]=5[CH3:43])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: NN
Solvent: CCO
Product: COc1ncc(-c2c(C)cc(C(=O)NN)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (EXAMPLE 34 Step A, 0.051 g, 0.067 mmol) was dissolved in ethanol (0.45 mL). Added hydrazine (0.063 mL, 2.014 mmol) and stirred at 85° C. in a screw cap vial (pressure relief type) under a nitrogen blanket. Once complete, the solvent was removed by rotary evaporation and the crude isolate was partitioned between ethyl acetate and water. Washed the organic twice more with water, then once with brine, dried over sodium sulfate, filtered and evaporated to give an off-white foam as the product. The compound was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.16 (s, 1H), 8.00 (d, 1H), 7.88 (s, 1H), 7.73 (s, 2H), 7.49 (s, 2H), 7.35 (s, 1H), 7.26 (d+s, 1H+CHCl3), 5.66 (d, 1H), 4.71 (d, 1H), 4.33 (m, 1H), 4.10 (m, 1H), 4.00 (s, 3H), 3.85 (m, 4H), 3.80 (m, 4H), 2.15 (s, 3H), 2.13 (s, 3H), 1.60 (br, 2H), 0.72 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]2[C@H:36]([OH:37])[CH2:35][CH2:34][O:33][CH2:32]2)[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]3[C@H:36]([OH:37])[CH2:35][CH2:34][O:33][CH2:32]3)=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(N[C@@H]2COCC[C@H]2O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2COCC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 75 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.03 g) in 2-propanol (20 mL) were added 1,5-anhydro-2,4-dideoxy-2-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]-threo-pentitol (980 mg) and piperidinium acetate (448 mg). The reaction mixture was stirred at 75° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (260 mg). Absolute configuration undetermined.