Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]([NH:11][NH:12][C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18](=[O:23])[NH:17][C:16]=1[CH3:24])=[O:14])=O)([CH3:4])([CH3:3])[CH3:2].S(Cl)([C:29]1C=CC(C)=CC=1)(=O)=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>O1CCCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[O:14][C:13]([C:15]2[C:16]([CH3:24])=[N:17][C:18]([O:23][CH3:29])=[C:19]([CH2:21][CH3:22])[CH:20]=2)=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C(=O)NNC(=O)CNC(=O)OC(C)(C)C)c(C)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(CNC(=O)OC(C)(C)C)o2)c(C)nc1OC
Temperature: 145 °C
Reaction time: 0.05 h
Yield: 182 %

Procedure:
Into each of three microwave vials is added {2-[N′-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hydrazino]-2-oxo-ethyl}-carbamic acid tert-butyl ester (190 mg, 0.519 mmol), tosyl chloride (119 mg, 0.624 mmol), and 2-t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol/g, 1.18 g, 2.6 mmol) and anhydrous tetrahydrofuran (6 mL). Each vial is flushed with nitrogen, sealed and heated in the CEM Discover microwave at 145° C. holding at that temperature for 3 min, with a maximum pressure of 7.3 bar. LC/MS shows the reaction is complete. The product from all three vials are filtered and washed with THF. The filtrate is evaporated, and the residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1). Fractions containing the product are combined again and evaporated to give [5-(5-ethyl-6-methoxy-2-methyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-ylmethyl]-carbamic acid tert-butyl ester (329 mg, 61% yield). MS: m/e 719 (95%) (2M+Na), 249 (100%) (M+H); 1H NMR (CDCl3, δ, ppm): 7.87 (1H, s), 5.15 (1H, br.), 4.61 (2H, br.d), 4.00 (3H, s), 2.79 (3H, s), 2.60 (2H, q), 1.49 (9H, s), 1.21 (3H, t).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][OH:14].[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:21][S:22]([O:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:9]=1[F:8])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1cc(F)c(F)cc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1cc(F)c(F)cc1F
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
Triethylamine (1.8 mL, 13.2 mmol) was added to a cold (0° C.) solution of a mixture of the 2-(2,4,5-trifluorophenoxy)ethanol (1.3 g, 6.6 mmol; from Step 3) and methanesulfonyl chloride (0.61 mL, 7.9 mmol) in dichloromethane (40 mL). After being stirred for 1.5 h, water was added and the mixture was concentrated. The residue was dissolved in EtOAc and the solution was washed with 1 M KHSO4, then with brine, dried (Na2SO4) and concentrated to give 1.78 g (quantitative yield) of the title compound as an orange oil. NMR analysis supports the stated structure. This material was used directly in the next step.
Reaction SMILES: N#N.C(OC([NH:10][C@H:11]([C:15]([NH:17][CH:18]([C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[CH:21]=1)[CH3:19])=[O:16])[CH:12]([CH3:14])[CH3:13])=O)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[S:24]1[C:20]([CH:18]([NH:17][C:15](=[O:16])[C@H:11]([CH:12]([CH3:13])[CH3:14])[NH2:10])[CH3:19])=[CH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]1=2
Reactant: CC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1cc2ccccc2s1
Agent: Cl
Agent: N#N
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: CC(NC(=O)[C@@H](N)C(C)C)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
11.3 g of N2 -tert-butoxycarbonyl-N1 -[1-(2-benzo[b]thienyl)ethyl]-L-valinamide was dissolved in 150 ml of ethyl acetate, and 20 ml of 6N hydrochloric acid was added to the resultant solution at room temperature. After agitating overnight at room temperature, the pH of the solution was adjusted to 7-8 with a saturated aqueous solution of sodium bicarbonate under water cooling. The ethyl acetate layer was then washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield a crude product. This crude product was then refined on FLORISIL® column chromatography to yield 6.7 g of the desired product, a white solid substance (melting point: 70°-71° C.).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10]C)=O.Cl.[NH2:13][C:14](=[NH:27])[CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]CC.[Na+]>C(O)C>[O:10]=[C:8]1[NH:27][C:14]([CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:13][C:2]2[CH2:7][CH2:6][O:5][CH2:4][C:3]1=2
Reactant: COC(=O)C1COCCC1=O
Reactant: N=C(N)CNC(=O)OCc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(NCc1nc2c(c(=O)[nH]1)COCC2)OCc1ccccc1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a solution of methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (51.1 g, 323 mmol) and benzyl 2-amino-2-iminoethylcarbamate hydrochloride (78.8 g, 323 mmol) in anhydrous ethanol was added sodium ethoxide (122 mL, 323 mmol, 21% in ethanol). The mixture was mechanically stirred, heated at reflux for 24 h, cooled down to ambient temperature, and filtered to give the title compound (55.6 g, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.40 (br. s., 1H), 7.69 (t, J=5.8 Hz, 1H), 7.15-7.44 (m, 5H), 4.99-5.08 (m, 2H), 4.35 (s, 2H), 4.04-4.11 (m, 2H), 3.84 (t, J=5.3 Hz, 2H), 2.48-2.57 (m, 2H). MS m/z 316.2 (M+1), retention time=1.10 min.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]Cl>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:18][C:19]4[C:32]5[C:31]([C:30]6[C:25]([C:24](=[O:34])[C:23]=5[CH:22]=[CH:21][CH:20]=4)=[CH:26][CH:27]=[CH:28][CH:29]=6)=[O:33])[C:15]=3[C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[O:17]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21
Temperature: 190 °C
Reaction time: 2 h

Procedure:
66 parts of 1-chloroanthraquinone, 60.5 parts of 1-aminoanthraquinone, 26.4 parts of sodium carbonate and 0.75 part of copper(I) chloride are suspended in 550 parts of nitrobenzene. With stirring, the mixture is heated to 190° C. and then a further 0.75 part of copper(I) chloride is added. The reaction mixture is heated to 206° C. and stirred for 3 hours at this temperature while distilling off the water of reaction. The batch is then heated to 214° C. and the pressure rises to about 1 bar. Stirring is continued for another 2 hours under these conditions. The reaction mixture is then cooled slightly and the nitrobenzene is removed by distillation. After drying there are obtained about 115 parts of anthrimide, which is suitable for further processing to give vat dyes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:16])[NH:9][N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:23]([N:9]1[C:8](=[O:16])[C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)n1[nH]c(=O)c2cnc(Cl)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c2cc(Cl)ncc2c(=O)n1Cc1ccccc1

Procedure:
Ethyl 6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (Intermediate 1B; 582 mg, 2.41 mmol), potassium carbonate (666 mg, 4.82 mmol), and benzyl bromide (0.345 mL, 2.9 mmol) were stirred in DMF (10 mL) at room temperature for 16 h. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave ethyl 2-benzyl-6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate. MS ESI calc'd. for C16H14ClN3O3 [M+1]+ 332. found 332. Ethyl 3-(benzyloxy)-6-chloro-1H-pyrazdo[4,3-c]pyridine-1-carboxylate was also obtained. MS ESI calc'd. for C16H14ClN3O3 [M+1]+ 332. found 332.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13]([C:15]3[C:19]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:18]([CH3:31])[S:17][C:16]=3[CH3:32])=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:33]([Sn](CCCC)(CCCC)CCCC)=[N+:34]=[N-:35].CC(O)=O>C1(C)C=CC=CC=1>[CH3:32][C:16]1[S:17][C:18]([CH3:31])=[C:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[C:15]=1[C:13]([NH:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]3[N:33]=[N:34][NH:35][N:2]=3)=[CH:8][CH:7]=2)[CH2:11][CH2:10]1)=[O:14]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1sc(C)c(C(=O)NC2(c3ccc(C#N)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1sc(C)c(C(=O)NC2(c3ccc(-c4nn[nH]n4)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of N-[1-(4-cyanophenyl)cyclopropyl]-2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]thiophene-3-carboxamide from Example 14, Step 2 (174 mg, 0.383 mmol) in toluene (2.5 mL), was added azidotributyltin (317 μL, 1.15 mmol) and the mixture was heated at the reflux temperature. After 20 h, the solution then obtained was allowed to cool to r.t. and AcOH (365 μL) was added. The heterogeneous mixture was stirred for 4 h and the precipitated solid was collected by filtration, successively rinsed with toluene and hexane then dried to afford the desired product as an off-white solid. MS (−APCI): m/z 496 (M−1)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=1.Cl.Cl[CH2:27][CH2:28][NH2:29].Cl[CH2:31][CH2:32]N>ClC1C=CC=CC=1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][CH:10]([C:4]2[CH:3]=[C:2]([N:1]3[CH2:32][CH2:31][NH:29][CH2:28][CH2:27]3)[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(N)cc(CC)c1
Reactant: NCCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(N2CCNCC2)c1
Yield: 63.3 %

Procedure:
A mixture of the ethyl (RS)-(3-amino-5-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (500 mg, 1.55 mmol) obtained in Example 223.4, bis-(2-chloroethylamine) hydrochloride (276 mg, 1.55 mmol) and chlorobenzene (5 ml) was heated under reflux for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2/MeOH 9:1). There were obtained 385 mg (63%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-piperazin-1-yl-phenyl)-acetate as a brownish solid; MS: 393 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH3:71])[CH2:42][CH2:43][C@@H:44]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH2:63])(=[O:62])=[O:61])=[CH:56][C:55]=1[S:64]([C:67]([F:70])([F:69])[F:68])(=[O:66])=[O:65])[CH2:45][S:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].ClCCl.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CO>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH3:71])[CH2:42][CH2:43][C@@H:44]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH:63][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)(=[O:61])=[O:62])=[CH:56][C:55]=1[S:64]([C:67]([F:70])([F:68])[F:69])(=[O:66])=[O:65])[CH2:45][S:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:33])[CH3:32]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 16 h
Yield: 78.8 %

Procedure:
To a yellow solution of (R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 1.64 g, 3.89 mmol), (R)-4-(4-((2-(tert-butyldimethylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 67, 2.68 g, 4.09 mmol), DMAP (0.95 g, 7.78 mmol) and dichloromethane (41 ml) was added EDC (1.492 g, 7.78 mmol). After stirring for 16 hours, the mixture was diluted with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 330 g SiO2, isocratic 50% ethyl acetate in hexanes for 50 minutes, then 50→65% ethyl acetate in hexanes over 30 minutes followed by 65→100% ethyl acetate in hexanes over 20 min and then 0→10% methanol in ethyl acetate over 20 minutes) to afford the title product (3.25 g, yield: 79%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH2:28]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[CH3:29].N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:3]1[N:4]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:28][CH3:29])=[CH:32][CH:33]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 99.8 %

Procedure:
A mixture of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.0 g), 4-ethoxyphenylboronic acid (2.8 g), copper(II) acetate (3.1 g), pyridine (3.1 mL), triethylamine (3.4 mL), molecular sieves 4 A (6.0 g) and dichloromethane (60 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (4.0 g, 100%) as a pale-yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#N)=[N:8]1)=[O:6].CCOC(C)=O>CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:7]2[CH2:11][CH2:10][C:9]([C:12]3[CH:13]=[C:14]([CH3:15])[CH:17]=[CH:18][CH:19]=3)=[N:8]2)=[O:6])[CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(C2=NN(C(=O)c3cccc(F)c3)CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc(C2=NN(C(=O)c3cccc(F)c3)CC2)c1
Yield: 35 %

Procedure:
3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzonitrile (88 mg, 0.30 mmol), dissolved in EtOH (10 mL) and EtOAc (10 mL) was passed through the H-cube equipped with a 10% Pd/C cartridge. Temperature 80° C., 50 bar, flow rate, 1 mL/min. LC-MS showed consumption of SM. The solvent was evaporated under pressure and the material was purified by chromatography using a 12 g silica cartridge eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. Amount obtained: 30 mg, 0.11 mmol, 35% yield. LC-MS (ESI) m/e 283 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.40 (s, 3H) 3.26-3.33 (m, 2 H) 4.27 (t, J=9.96 Hz, 2 H) 7.17-7.26 (m, 2 H) 7.32 (t, J=7.81 Hz, 1H) 7.43 (td, J=7.98, 5.81 Hz, 1H) 7.49-7.54 (m, 2 H) 7.73-7.84 (m, 2 H).
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:17])[NH:10][N:9]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C(OCC)C>O>[C:18]1(=[O:23])[N:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:17])[NH:10][N:9]=2)[C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1n[nH]c2cccc(Cl)c12
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(Cl)c12
Yield: 99.1 %

Procedure:
To 50 ml of dioxane were added 5.66 g of 3-amino-4-chloroindazole thus obtained and 6.68 g of phthalic anhydride, and the mixture was stirred for 5 hours at 120° C. After the mixture was condensed under reduced pressure, the condensed residue was added with 30 ml of diethyl ether and stirred under cooling with ice and water for 30 minutes to separate crystals. Then the crystals were obtained by filtration and dried under reduced pressure to give 9.96 g of 3-phthalimido-4-chloroindazole having the following analytical values in a yield of 89%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([NH2:20])=[O:19].N1C=CC=CC=1.[CH2:27]([O:31][CH2:32][C:33](Cl)=O)[CH:28]([CH3:30])[CH3:29].[OH-].[Na+]>C1COCC1>[CH2:27]([O:31][CH2:32][C:33]1[NH:20][C:18](=[O:19])[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[N:7][C:2]=2[N:1]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)nc1N
Reactant: CC(C)COCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid amide (0.5 g, 1.75 mmol) in anhydrous THF (25 mL) under N2 atmosphere. Add dropwise pyridine (0.325 mL, 4.0 mmol) and isobutoxyacetyl chloride (0.2 mL, 4.04 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and stir at 50° C. for 4 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and purify by column chromatography to give 2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][CH2:42][C:43]([NH2:45])=[O:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8](=[O:40])[NH:41][CH2:42][C:43]([NH2:45])=[O:44])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: NCC(N)=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCC(N)=O)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using (S)-phenyl(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate (intermediate 32) (100 mg, 0.18 mmol) and 2-aminoacetamide (20 mg, 0.27 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound as a yellow solid. (4 1 mg, 43%)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].O.C([O-])([O-])=O.[Na+].[Na+].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:24](Cl)=[O:25])=[CH:18][CH:17]=1>C1COCC1>[CH2:22]([O:23][C:24]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7])=[O:25])[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a stirred solution of (S)-pyrrolidine-2-carboxylic acid (7) (2.0 g, 17.39 mmol) in THF:H2O (20 mL, 1:1) were added Na2CO3 (2.76 g, 26.08 mmol) and Cbz-Cl (3.54 g, 20.80 mmol) and stirred at RT for 18 h. The reaction mixture was washed with EtOAc (10 mL) and the aqueous layer was acidified with 3N HCl and extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield compound 8 (3.0 g, 69.7%).
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11](I)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[CH2:29]([N:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11]([C:39]3[CH:38]=[N:37][N:36]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:40]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Reactant: CC(=O)N1c2ccc(I)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1
Product: CC(=O)N1c2ccc(-c3cnn(Cc4ccccc4)c3)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1

Procedure:
rac-cis-1-Acetyl-6-(1-benzyl-1H-pyrazol-4-yl)-2,3-bis-(4-chloro-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-1-acetyl-2,3-bis-(4-chloro-phenyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 1-benzyl-1H-pyrazole-4-boronic acid. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 555.17; the expected mass is 554.1. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:24])[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:25]N(C=O)C>>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:25])[C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:24])[N:16]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)c(C#N)cc1F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Sodium hydride (0.11 g, 4.65 mmol) was added to a solution of 6-[(3-{[tert-butyl(dimethyl)-14-silyl]oxy}propyl)amino]-2-chloro-5-fluoronicotinonitrile (Example 309, 0.80 9, 2.33 mmol) in DMF (23.26 mL). The mixture was stirred at rt for 30 min, and then Mel (0.58 mL, 9.30 mmol) added. The reaction mixture was stirred at rt for 18 h, quenched with water, and the aqueous phase was extracted with ether. The combined ether extracts were washed with water, brine, and then dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.88 g, 99%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.53 (d, 1H), 3.70-3.60 (m, 4H), 3.17 (d, 3H), 1.84-1.76 (m, 2H), 0.84 (s, 9H), 0.00 (s, 6H).