Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+].ClC1C=CC(C2C(C3C=CC(Cl)=CC=3Cl)=CN3C(CC4C=NC(C(F)(F)F)=CC=4)=NN=C3C=2)=CC=1>O1CCOCC1.O.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>[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Reactant: COc1ccc(B(O)O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cn3c(Cc4ccc(C(F)(F)F)nc4C)nnc3cc2-c2ccc(Cl)cc2)c(Cl)c1
Yield: 69 %

Procedure:
The title compound (7.5 mg, 70%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2-chloro-4-methoxyphenyl-boronic acid (7.3 mg, 0.039 mmol), K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time=1.97 min [M+H]+=543.3.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].FC(F)(F)C(O)C.[OH-].[Na+]>CCOCC>[C:1]([C:3]1[C:4]([O:13][CH:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cnc(OC(C)C(F)(F)F)c(C#N)c1
Agent: CC(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(Oc1ncc(C(=O)O)cc1C#N)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 363 mg (1.32 mmol) of methyl 5-cyano-6-(2,2,2-trifluoro-1-methylethoxy)nicotinate (from Step C) and 5.0 mL of 1,1,1-trifluoro-2-propanol in 5.0 mL of Et2O was added 530 μL (2.65 mmol) of 5.0 N NaOH. After stirring at rt overnight, the mixture was diluted with Et2O (20 mL), washed with diluted HCl (2×10 mL), dried over Na2SO4, and concentrated to give 327 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 1.46 (d, J=6.4, 3H), 5.92 (m, 1H), 8.52 (d, J=2.1, 1H), 8.86 (d, J=2.0, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[N:5]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: COCc1n[nH]cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nn(-c2cc(C(F)(F)F)ccn2)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (1.8 g) synthesized in Example 29(1) in N,N-dimethylformamide (20 mL) were added 2-chloro-4-trifluoromethylpyridine (2.0 g) and potassium carbonate (2.3 g), and the mixture was stirred at 100° C. overnight. The reaction mixture was allowed to cool to room temperature and filtered through celite, water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.62 g, 18%) as a pale-yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:16][C:17]1[S:18][C:19]([Cl:22])=[CH:20][N:21]=1.Cl>N1C=CC=CC=1>[Cl:22][C:19]1[S:18][C:17]([NH:16][S:2]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[N:21][CH:20]=1
Reactant: Nc1ncc(Cl)s1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(chlorosulfonyl)benzoate (Preparation 2, 8.0 g, 34 mmol, 1 eq) was added portionwise to a solution of 2-amino-5-chlorothiazole hydrochloride (23.3 g, 136 mmol, 4 eq) in pyridine (80 ml) and the reaction mixture stirred at room temperature for 1 hour. The solution was added to a stirred solution of 6M HCl (300 ml) and the resulting precipitate collected by filtration and washed with water. The title compound was obtained as a dark brown solid (3.35 g, 0.01 mmol, 30%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:28][C:29]([CH3:32])=[CH:30][N:31]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[C:26]([CH3:25])=[N:31][CH:30]=[C:29]([CH3:32])[N:28]=4)[CH2:34][CH2:35]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)n1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (CAS 59215-42-8) to give the title compound as a colorless solid. MS: 526.8 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([Sn](CCCC)(CCCC)CCCC)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:26]([S:29]([N:32]1[C:36]2[CH:37]=[C:38](I)[CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH2:42])(=[O:31])=[O:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH:26]([S:29]([N:32]1[C:36]2[CH:37]=[C:38]([C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH2:42])(=[O:30])=[O:31])([CH3:28])[CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(C)nc1-c1ccccc1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(I)cc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)c(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)s1
Temperature: 25 °C
Yield: 2 %

Procedure:
Stir a mixture of 2-methyl-4-phenyl-5-(tributylstannyl)thiazole (0.1 g, 0.21 mmol), 1-isopropylsulfonyl-2-amino-6-iodobenzimidazole (0.07 g, 0.21 mmol), and (acetonitrile)palladium(II) chloride (0.021 mmol) in dry dimethylformamide (2 mL) at 100° C. for 4 hours under a nitrogen atmosphere. Cool to room temperature and dilute with ethyl acetate (20 mL). Wash sequentially with water (3×5 mL) and saturated aqueous sodium chloride (3×5 mL), dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 7:1 dichloromethane:acetonitrile to provide the title compound as a white solid in 2% yield. MS(ES+): m/z=413.0 (M+H)+
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[O:5].[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28](O)=[O:29])=[CH:22]2>>[CH2:11]([C@H:3]([NH:2][C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:18])=[CH:27][CH:26]=2)=[O:29])[C:4](=[O:5])[N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one hydrochloride (2.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.6 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 96 hour reaction time, washed with acid first then base). The crude product was triturated with 1:1 ether-hexanes and dried. Yield 966 mg, 91%; HPLC (60/40) 7.99 minutes (97%); PBMS 414/416 (MH+, 100%);
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16].CCN(CC)CC.O>C(Cl)(Cl)Cl>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1c(F)cccc1F
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Yield: 76.2 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (11.1 g, 50 mmol) in CHCl3 (100 mL) was added 2,6-difluoroaniline (8.07 mL, 75 mmol, 1.5 eq) followed by Et3N (10.43 mL, 75 mmol, 1.5 eq). The reaction mixture turned yellow and was heated to reflux for 24 h, H2O (50 mL) was added and the layers were separated. The organic layer was evaporated and the crude product was recrystalized from 200 mL of a methanol: H2O mixture (2:1) to give 12.03 g (76%) of pure 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.21 (s, 3H), 6.91 (m, 2H), 7.24 (m, 1H), 10.29 (s, 1H), 10.35 (br s, 1H). LC MS (m/e)=316 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:15][C@@H:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].O>CO>[C@@H:16]1([N:15]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:27](=[O:30])[CH:28]=[CH2:29])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: CCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CC(=O)N(CCCCCCCC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.42 h

Procedure:
62.5 mmol (6.63 g) of sodium carbonate are added to 24 mmol (7 g) of N-octyl-β-D-glucopyranosylamine in 100 ml of methanol at 30° C.; 48 mmol (3.9 ml) of acryloyl chloride are run in at 0° C. over 5 minutes into the heterogeneous mixture. The reaction mixture is left at ambient temperature with stirring for 25 minutes. After addition of 100 ml of water and evaporation of the methanol the acrylamidosugar is extracted with 300 ml of ethyl acetate. The organic phase is washed with a saturated solution of NaHCO3. dried over MgSO4 and evaporated at reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cl:21][C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][C:27]=1[C:28]([C:30]1[CH:40]=[C:39]([CH3:41])[C:33]2[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29].CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]Br>[Cl:21][C:22]1[N:23]=[N:24][C:25]([N:15]2[CH2:14][CH2:13][CH:12]([N:9]3[CH2:10][CH2:11][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=4[NH:7][C:8]3=[O:18])[CH2:17][CH2:16]2)=[CH:26][C:27]=1[C:28]([C:30]1[CH:40]=[C:39]([CH3:41])[C:33]2[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=2[CH:31]=1)=[O:29]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)n(C)c12
Agent: [Cu]Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c(Cl)nn3)CC1)C(=O)N2

Procedure:
550 mg (2.00 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 610 mg (1.80 mmol) 6-(3.6-dichloro-pyridazine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one, 630 mg (4.39 mmol) copper(I)bromide and 430 mL (2.50 mmol) DIPEA in 5 mL DMF were stirred for 2 h at 110° C., then cooled and filtered. The filtrate was combined with 1 mL of a 1N aqueous hydrochloric acid solution and precipitated with 40 mL ice water. The precipitate was suction filtered, washed with water and dried. The solid was stirred with 120 mL DCM/MeOH (11:1), filtered through silica gel and washed with DCM/MeOH. The filtrate was evaporated down. The residue was triturated with diethyl ether, suction filtered and dried. A mixture of isomers was obtained which was further reacted.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1)([CH3:3])[CH3:2].[I:22]N1C(=O)CCC1=O.O>C(#N)C>[I:22][C:15]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)[Si](OCc1cn2ccccc2n1)(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)[Si](OCc1nc2ccccn2c1I)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
1.85 g (6.08 mmol) of 2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were solubilised in 25 ml of acetonitrile with magnetic stirring, to this solution were added 1.409 g (6.08 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h before being treated with 100 ml of water. The aqueous phase was extracted with 3×50 ml of dichloromethane. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 2.29 g (yield=83%) of 3-iodo-2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were obtained as a pale yellow solid. LC-MS: m/z=431 (MH+); UV purity at 254 nm=95%.
Reaction SMILES: [C:1]([CH:6]([CH2:10]C#C)[C:7](=O)[CH3:8])([O:3][CH2:4][CH3:5])=O.C(=O)(O)O.[NH2:17][C:18](N)=[NH:19].C(O)C.CC(C)=O>CS(C)=O>[CH3:8][C:7]1[C:6]2[CH:10]=[C:4]([CH3:5])[O:3][C:1]=2[N:17]=[CH:18][N:19]=1
Reactant: C#CCC(C(C)=O)C(=O)OCC
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(C)=O
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc2c(C)ncnc2o1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 6.0 g 3-carbethoxy-5-hexyn-2-one and 3.6 g guanidine carbonate was heated in 9 ml dimethylsulfoxide under a nitrogen atmosphere at 140° for 4 hours. The ethanol produced in the reaction was removed as it was formed by distillation. After cooling to room temperature, acetone was added then the crystalline solid was collected then rinsed with water to yield 2.6 g of 4,6-dimethylfuro[2,3-d]pyrimidine; m.p. 262°-263°. Absorptions at 2.55 (singlet), 2.82 (singlet) and 6.58 (broadened singlet) ppm in the nuclear magnetic resonance spectrum (60 MHz) indicated the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20]O)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20][N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN1CCNCC1
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Product: CN1CCN(Cc2cc(Nc3ccnc4cc(Cl)ccc34)ccc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (compound of step C of example 31) (0.105 g, 0.26 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to 4-methylpiperazine (0.86 mL, 7.75 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (Et2O/MeOH/NH4OH//80/20/1) to yield expected compound as a yellow solid (120 mg, 99% yield). LC-MS: m/z (ESI) 452.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:7]([CH3:9])=O)C.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[CH3:9][C:7]1[C:6]([CH2:5][C:4]([OH:3])=[O:19])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]=1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccc2)c(-c2ccc(Cl)cc2)c1CC(=O)O
Yield: 72.2 %

Procedure:
11.5 grams 3-(p-chlorobenzoyl)-levulinic acid ethyl ester, 4.9 grams phenyl-hydrazine, 2.8 grams glacial acetic acid and 10 milliliters ethanol were mixed an the mixture was heated to the boiling temperature under reflux for 3.5 hours. The reaction mixture was evaporated and 100 milliliters benzene were added to the residue. The pH of the solution was adjusted to 3, followed by extraction with water. The benzene phase was evaporated and 30 milliliters ethanol and 20 milliliters 2n aqueous sodium hydroxide added to the residue. The mixture was heated to the boiling temperature under reflux for 1 hour, and thereafter worked up and the free acid recovered in accordance with a procedure analogous to that set out in Example (1b). 9.6 grams 3-methyl-1-phenyl-5-(p-chlorophenyl)pyrazol-4-acetic acid, melting at 174°-177° C., were obtained representing a yield of 72%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]#[N:30])=O)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:70]=[N+:71]=[N-:72])(C)C>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]4[N:26]([CH2:27][CH2:28][C:29]#[N:30])[N:72]=[N:71][N:70]=4)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NCCC#N)s3)C[C@H]2OC)nc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(-c4nnnn4CCC#N)s3)C[C@H]2OC)nc1Cl
Yield: 39.6 %

Procedure:
THF (2 mL) was added to cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-N-(2-cyanoethyl)-4-methyl-1,3-thiazole-5-carboxylic acid amide obtained in Example (261a) (36 mg, 0.08 mmol). While the mixture was stirred, triphenylphosphine (124 mg, 0.47 mmol), diisopropyl azodicarboxylate (0.24 mL, 0.45 mmol, 1.9 M solution in toluene) and trimethylsilyl azide (7.3 g, 55.4 mmol) were added, followed by stirring at 30° C. for four days. The reaction solution was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0/10, 2/8) and preparative thin layer chromatography (developing solvent: ethyl acetate/hexane=10/1) to obtain 16 mg of the title compound as a white solid (41%).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[OH:19][NH3+:20].C([O-])(=O)C.[Na+].O>C(O)C.C(OCC)(=O)C>[N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[N:20][OH:19])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [NH3+]O
Reactant: O=C1CCCc2ccc(N3CCOCC3)cc21
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: ON=C1CCCc2ccc(N3CCOCC3)cc21
Yield: 100.2 %

Procedure:
A solution of 7-morpholin-4-yl-3,4-dihydro-2H-naphthalen-1-one (360 mg), hydroxylammonium chloride (163 mg) and sodium acetate (384 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour and 50 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 384 mg of the title compound as a crude product. The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1.CS(C)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1NC1CC1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoic acid ethyl ester (Example 2c, 9.34 g, 23.1 mmol), cyclopropylamine (16 mL, 228 mmol), and dimethyl sulfoxide (30 mL) is heated in a sealed tube at 110° C. for 3 days. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford a brown residue. The residue is then purified via flash column chromatography (1:1 ethyl acetate/hexanes) to afford the title compound (4.41 g). MS CI: m/z 442 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[O:11])([O-:3])=[O:2].[H-].[Na+].CN(C)[C:29](Cl)=[O:30].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10](=[O:11])[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH3:17])[C:29]2=[O:30])[CH:22]=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CN(C)C(=O)Cl
Reactant: CCOCCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
3.3 g of 2-(m-nitroanilino)-N-(2-ethoxyethyl)benzamide was dissolved in 30 ml of dry tetrahydrofuran, and to the solution was added 1.0 g of approximately 50 % sodium hydride. After stirring the mixture for 30 minutes, 3.2 g of N,N-dimethylcarbamoyl chloride was further added dropwise under cooling, and the whole was refluxed for 4 hours. After the reaction was complete, the solvent was evaporated from the resulting mixture under reduced pressure. To the residue thus obtained was added water to yield a crude product. This product was recrystallized from ethanol to give 3.1 g of 1-(m-nitrophenyl)-3-(2-ethoxyethyl)quinazoline-2,4(1H, 3H)-dione as pale yellow prisms, melting at 161°-162° C.