Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:25]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: O=C(OC(C(=O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
1 g of desyl benzoate and 0.5 g of thiourea (2 eq.) are added to 10 ml of dimethylformamide in a reactor. The solution is left stirring at 160° C. for 7 hours.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]1([C@H:14]([NH2:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[C:8]1([CH:14]([NH:16][C:5](=[O:7])[CH3:6])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)c1ccccc1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
Acetic anhydride (38.4 g) was dropwise added to a solution (200 ml) of (R)-(+)-1-phenylethylamine (30 g) in chloroform under ice-cooling. After completion of the reaction, ice water was added thereto and the mixture was extracted with chloroform. The extract was washed with 1N aqueous solution of sodium hydroxide and water. After drying, the mixture was concentrated under reduced pressure to give crystals, which were recrystallized from isopropyl ether to give 32.2 g of (+)-N-(1-phenylethyl)acetamide. [α]D =+143.5° (ethanol, c=1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]([Cl:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][CH3:18]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([N:17]([CH3:18])[CH3:16])[N:10]=[C:9]([Cl:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Reaction time: 2 h

Procedure:
A red to brown solution of 2,6-dichloro-isonicotinic acid tert.-butyl ester (1.49 g, 6.0 mmol) in 2 M dimethylamine in THF (20 mL) is stirred at 65° C. for 2 h, then at 80° C. for 2 h and finally at 110° C. for 12 h in an autoclave. The mixture is concentrated to give crude 2-chloro-6-dimethylamino-isonicotinic acid tert-butyl ester (2.0 g) as a brown residue; LC-MS: tR=1.08 min, [M+H]+=257.32; 1H NMR (D6-DMSO): δ 1.54 (s, 9H), 3.06 (s, 6H), 6.85 (s, 1H), 6.92 (s, 1H).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].[Cl:13][C:14]1[C:19](O)=[C:18]([Cl:21])[C:17]([Cl:22])=[C:16]([Cl:23])[C:15]=1[Cl:24].O=P(Cl)(Cl)Cl.Cl>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[C:19]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:18]([Cl:21])[C:17]([Cl:22])=[C:16]([Cl:23])[C:15]=1[Cl:24]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: N#CC(C(=O)O)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
8 g. (0.05 moles) of α-cyanophenylacetic acid, 13 g. (0.05 moles) of pentachlorophenol are mixed together. 4.3 g. (0.05 moles) of phosphoroxychloride are added dropwise. The obtained mixture is heated slowly to 85°-90° C. on an oil-bath and the mixture is kept at this temperature until the HCl evolution ceases. When the reaction is completed, the mixture is cooled to room temperature, and the melt is taken up in 100 ml. of carbon tetrachloride. The solution is washed three times with 30 ml. of water, treated with decolorizing charcoal, dried and evaporated. The product is recrystalized from diisopropyl ether, and crystalline pentachlorophenyl ester is precipitated.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=3)[C:19](=O)[C:18]3[C:17]([C:28](OCC)=[O:29])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)=[O:4].O.[NH2:35][NH2:36]>>[CH3:33][N:2]([CH3:1])[C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:29])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(=O)N(C)C)cc1)N2
Solvent: O
Product: CN(C)C(=O)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
Ethyl 2-(4-(dimethylcarbamoyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (500 mg, 1.12 mmol) and hydrazine monohydrate (8 mL) were added and the mixture was stirred under 40° C. for 3 h. Then the mixture was cooled to room temperature and filtered to give the title compound (90 mg, yield 19%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.86 (s, 3H), 2.96 (s, 3H), 3.42 (s, 3H), 4.66-4.69 (d, J=10.4 Hz, 1H), 4.96-4.99 (d, J=10.4 Hz, 1H), 6.73 (s, 1H), 6.89 (s, 1H), 7.16-7.19 (m, J=7.6 Hz, 1H), 7.29-7.45 (m, 6H), 7.56-7.60 (t, J=7.6 Hz 1H), 12.18 (s, 1H); LC-MS (ESI) m/z: 415 (M+1)+.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9]2)[CH2:5][CH2:4]1)#N.[OH-].[Na+].[ClH:28]>C(O)(=O)C>[ClH:28].[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2([CH2:5][CH2:4][NH:3][CH2:8][CH2:7]2)[CH2:9]1)([O-:25])=[O:24]
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccccc21

Procedure:
A slurry of 14.62 g of 1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] of Example 37 in 100 ml of glacial acetic acid and 190 ml of 3N aqueous hydrochloric acid is heated at reflux for 18 hours, the mixture becomes homogeneous at 70°-80° C. The mixture is made basic using aqueous sodium hydroxide and extracted with chloroform. The organic portions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give a solid comprising the free base of the product. The salt is prepared from the freshly alkali washed and dried free base using chloroform/ethereal hydrochloric acid, to yield the product mp, 222°-224° C. of 1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[O:19]1[CH:23]=[N:22][N:21]=[C:20]1[CH2:24][CH2:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([CH2:25][CH2:24][C:20]3[O:19][CH:23]=[N:22][N:21]=3)=[CH:27][CH:28]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnccc1-c1ccc(F)cc1
Reactant: Nc1ccc(CCc2nnco2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1cnccc1-c1ccc(F)cc1)Nc1ccc(CCc2nnco2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.5 %

Procedure:
A mixture of (2E)-3-[4-(4-fluorophenyl)pyridin-3-yl]prop-2-enoic acid (18.0 g), 4-[2-(1,3,4-oxadiazol-2-yl)ethyl]aniline (14.0 g), triethylamine (14.97 g), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (18.84 g) and dichloromethane (2.5 L) was stirred at room temperature for 17 hr. The reaction mixture was washed successively with water and 1 M aqueous sodium hydroxide solution. Methanol (600 mL) was added thereof, and the mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid. The obtained solid was recrystallized with ethanol to give the title compound (25.0 g).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[S:31])[CH:24]=1>>[CH3:32][C:23]1[CH:24]=[C:25]([NH:29][C:30]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:31])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(N=C=S)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(C)c4)CC3)nc21

Procedure:
Pipemidic acid (54 mg, 0.177 mmol) and m-tolylisothiocyanate (20 μL, 0.148 mmol) were used. Purification on silica yielded compound 13 in Table 1, below (67 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.68 (s, 1H), 7.34-7.32 (m, 1H), 7.05-6.94 (m, 3H), 4.33 (q, J=7.10 Hz, 2H), 4.24-3.87 (m, 8H), 2.35 (s, 3H), 1.49 (t, J=7.19 Hz, 3H) ppm.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH2:30])=[CH:28][C:23]=2[O:22][CH2:21]1.CCN(C(C)C)C(C)C>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][C:3]3[S:4]/[C:5](=[CH:9]\[C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][CH:14]=[CH:13]5)/[C:6](=[O:8])[N:7]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2ccc3c(c2)OCO3)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, benzo[1,3]dioxol-5-ylmethyl amine and DIEA to give 2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].CI.[C:17](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:17])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 66.1 g (0.341 mole) of methyl 5-acetyl-2-hydroxybenzoate, 7.26 g (0.511 mole) of methyl iodide and 47.0 g (0.341 mole) of potassium carbonate in 400 ml of sieve-dried dimethylformamide is stirred at room temperature for 65 hours. The mixture is poured on 1.5 liters of N hydrochloric acid, extracted 6 times with ethyl ether, washed extract with water, NaHCO3 solution and cold 1 N NaOH, dried over Na2SO4, and evaporated solvent. Methyl 5-acetyl-2-methoxybenzoate, 51.3 g (72%) m.p. 95°-96° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.I[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34]([CH3:36])=[N:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([NH:28][C:29]5[CH:39]=[C:38]([CH3:40])[C:32]6[N:33]([CH3:37])[C:34]([CH3:36])=[N:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Nc2cc(I)ncn2)cc2nc(C)n(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5c(c4)nc(C)n5C)ncn3)CC1)C(=O)N2
Temperature: 150 °C

Procedure:
80 mg (0.29 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.10 g (0.26 mmol) (6-iodo-pyrimidin-4-yl)-(1,2,7-trimethyl-1H-benzimidazol-5-yl)-amine and 0.15 mL (0.87 mmol) DIPEA were combined in 1.5 mL DMF and stirred at 150° C. The reaction mixture was then purified by preparative HPLC. The product-containing fractions were combined, evaporated down and the residue was dried. This was taken up in DMF and purified again by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[C:10]=1[Cl:11])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([CH3:36])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[C:10]=1[Cl:11])[C:5]([NH:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([CH3:36])[CH:27]=1)=[O:7]
Reactant: CC(C)Oc1cc(C(=O)O)cc(Cl)c1Cl
Reactant: COC(=O)c1ccc(N)cc1C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)c(OC(C)C)c2)cc1C
Yield: 68 %

Procedure:
Methyl 4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10) (237 mg, 68%) was prepared from 3,4-dichloro-5-isopropoxybenzoic acid (8) (200 mg, 800 μmol) using a procedure essentially the same as in step (i) for AAA-064 except that DIPEA was used instead of TEA, and methyl 4-amino-2-methylbenzoate (9) was used instead of methyl 4-amino-2-fluorobenzoate: m/z 396 [M+H]+ (ES+), 394 [M−H]− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, s), 7.89 (1H, d), 7.81 (1H, d), 7.77-7.72 (2H, m), 7.64 (1H, d), 4.85 (1H, sep), 3.81 (3H, s), 2.54 (3H, s), 1.35 (6H, d).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH2:6][O:7]2.[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>ClCCCl>[CH2:22]([O:21][C:19]([CH:18]1[CH:4]2[CH:5]1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:2]([OH:1])[C:3]=12)=[O:20])[CH3:23]
Reactant: CCC(=O)c1ccc2c(c1O)C=CCO2
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCCl
Product: CCOC(=O)C1C2COc3ccc(C(=O)CC)c(O)c3C21
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
To a mixture of 1-(5-hydroxy-2H-chromen-6yl)-propan-1-one (511 mg, 2.5 mmol) and (Rh(II)Ac2)2 (11 mg, 0.025 mmol) in 1,2-dichloroethane (8 mL) at 20° C., was added dropwise (3 h) a solution of ethyl diazoacetate (571 mg, 5 mmol) in 1,2-dichloroethane (2 mL). After 15 min at 20° C., the reaction mixture was washed with H2O (10 mL). The H2O phase was washed with CH2Cl2 (10 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, 1→5% MeOH in CH2Cl2), to give 300 mg (41%) of 7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid ethyl ester (a 33/64 mixture of cis and trans isomers).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][CH3:21])=[O:13].[Br:22][CH2:23][C:24](Cl)=[O:25]>ClCCl.O>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH3:21])[C:24](=[O:25])[CH2:23][Br:22])=[O:13]
Reactant: O=C(Cl)CBr
Reactant: CNc1ccccc1C(=O)c1c(OC)cc(C)cc1OC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1C(=O)c1ccccc1N(C)C(=O)CBr
Temperature: -10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a mixture of 10 g of (2,6-dimethoxy-4-methylphenyl)(2-methylaminophenyl) ketone in 100 ml of dichloromethane and 20 ml of water, cooled to -10° C., are added dropwise 6.34 g of bromoacetyl chloride in 20 ml of dichloromethane. The reaction mixture is allowed to return to room temperature and is then stirred vigorously for 2 hours. The phases are separated after settling has taken place and the organic phase is successively washed with water, dried over sodium sulphate and evaporated to dryness to give beige crystals melting at 121° C.; Yield=99%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][CH:15]([CH:31]([CH3:33])[CH3:32])[C:16]([N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17]>>[CH2:24]([N:18]([CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])[C:16](=[O:17])[C@@H:15]([NH:14][C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[O:11])[CH:31]([CH3:32])[CH3:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)C(N)C(=O)N(CCN(C)C)Cc1ccccc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CC(C)[C@H](NC(=O)Nc1ccc(C(F)(F)F)cc1)C(=O)N(CCN(C)C)Cc1ccccc1

Procedure:
Compound 14c was prepared from 4-(trifluoromethyl)phenyl isocyanate and compound 13, using the method described in Example 22. MS (EI)=464 (M+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.5 %

Procedure:
To a solution of Example 12 (0.230 g, 0.556 mmol) in methanol (3.5 ml), lithium hydroxide (0.132 g, 5.56 mmol) in water (0.9 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.130 g, 61%). M.P.: 254-257° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.43 (s, 1H), 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.38 (d, J=7.5 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.19 (m, 2H), 8.04 (m, 3H), 7.83 (dd, J=8.8, 2.0 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.23 (s, 2H). MS (m/z): 400.01 (M++1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>[Fe].CCO>[F:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1)[NH2:9]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCCC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCCC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Iron powder (61.42 g, 1 mol) and hydrochloric acid (6 mL) were added to 90% EtOH (25 v/w, 1210 mL). The mixture was warmed up to 80° C. and stirred for 15 min. Then Intermediate VIII (48.42 g, 0.11 mol) was added in batch to the reaction solution. After the addition completion, the reaction was conducted under reflux for 2 h. After completion of the reaction, the reaction was filtered by suction when h is still hot. The filtrate was collected. The solvate was evaporated off to produce a yellow solid (43 g) in a yield of 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:42][CH:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:28])[N:48]3[CH2:49][CH2:50][N:45]([CH:43]([CH3:44])[CH3:42])[CH2:46][CH2:47]3)[N:9]=2)[CH:7]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added DIEA (126 mg, 0.97 mmol), 1-(propan-2-yl)piperazine (126 mg, 0.98 mmol) and HATU (185 mg, 0.49 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=40:60 within 14 min; Detector, UV 254 nm. This resulted in 51.6 mg (28%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(propan-2-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=573.2, RT=1.80 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.2, 6.9 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 9.0 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.52-3.48 (m, 4H), 2.78-2.65 (m, 1H), 2.46-2.39 (m, 4H), 1.09-0.97 (d, 6H, J=6.6 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](=O)[CH2:9][CH3:10])[CH2:4][CH2:3]1.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1>>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:9][CH3:10])=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)C1CCC(O)CC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)C1CCC(O)CC1
Yield: 52 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(4-hydroxycyclohexyl)propan-1-one (0.6 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.6 g, 1.5 eq) to give 0.8 g desired product (52% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.11-7.20 (m, 1H), 7.00-7.10 (m, 2H), 6.90-6.70 (m, 1H), 6.60-6.89 (m, 3H), 6.58 (d, J=7.6 Hz, 1H), 4.08-4.20 (m, 2H), 3.70-3.80 (m, 2H), 3.60 (brs, 1H), 2.47 (q, J=7.6 Hz, 2H), 2.28-2.38 (m, 1H), 2.00-2.08 (m, 2H), 1.86-1.94 (m, 2H), 1.72-1.80 (m, 1H), 1.20-1.49 (m, 4H), 1.04 (t, J=7.6 Hz, 3H)
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCCN1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (D108, 2.07 g, 6.1 mmol) in 16 ml of dichloromethane, cooled to 0° C., were added 4 ml of TFA. The reaction mixture was allowed to warm-up to r.t. and then it was stirred at this temperature for 30 mins. The title compound (1.06 g, y=88%) was isolated after purification by SCX.