Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[C:9]([C:11]([NH:13][CH3:14])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[C:24]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:29]=1)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:35]([NH:34][C:30]4[CH:29]=[C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:33]=[CH:32][N:31]=4)=[O:36])=[CH:17][CH:16]=3)[C:9]([C:11]([NH:13][CH3:14])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CNC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccnc(NC(=O)Oc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(C)(C)C)ccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of DMF (1 mL) was added Intermediate X (50 mg, 0.18 mmol) followed by phenyl (4-tert-butylpyridin-2-yl)carbamate (48 mg, 0.18 mmol) and triethylamine (25 μL, 0.18 mmol). The reaction was stirred at rt overnight, concentrated to dryness, and purified by HPLC to afford 22 mg of the above compound (0.04 mmol, yield 26%). 1H-NMR (DMSO-d6) δ 10.9 (s, 1H), 9.48 (s, 1H), 8.17 (d, J=5.4 Hz, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.02 (d, J=5.0 Hz, 1H), 7.61 to 7.54 (m, 3H), 7.29 (d, J=8.3 Hz, 2H), 7.04 (dd, J=5.5, 1.6 Hz, 1H), 2.61 (d, J=4.7 Hz, 3H), 1.25 (s, 9H); MS [M+H]+=459.2; LCMS RT=2.49.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2].[O:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40]>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:37]3[CH2:38][CH2:39][O:35][C:36]3=[O:40])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Reactant: O=C1NCCO1
Product: CC(=O)N1CCN(c2cc(N3CCOC3=O)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Yield: 3.6 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (342 mg) described in Preparation Example 196 and oxazolidin-2-one (61.8 mg), the title compound (13.6 mg) was obtained.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[CH3:5][NH+:6]1[CH2:10][CH2:9][N:8]([CH3:11])[CH:7]1Cl.[CH3:13][N-:14][CH3:15].[Li+]>C(#N)C>[N+:1]([O-:4])([O-:3])=[O:2].[CH3:5][NH+:6]1[CH2:10][CH2:9][N:8]([CH3:11])[CH:7]1[N:14]([CH3:15])[CH3:13]
Reactant: CN1CC[NH+](C)C1Cl
Reactant: C[N-]C
Agent: O=[N+]([O-])[O-]
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C1N(C)CC[NH+]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
3.00 g (15.34 mmol) of 1,3-dimethyl-2-chloroimidazolidinium nitrate and 0.78 g (15.29 mmol) of lithium dimethylamide are dissolved in 20 ml of acetonitrile under a protective-gas atmosphere (argon). The reaction mixture is stirred for 5 hours at room temperature, and LiCl is subsequently filtered off. The salt LiCl is washed with 5 ml of acetonitrile, and the organic phases are combined. The solvent is distilled off, and the residue is dried under reduced pressure at 7 Pa and 50° C., giving 2.91 g of 1,3-dimethyl-2-dimethylaminoimidazolidinium nitrate as a liquid, corresponding to a yield of 92.2%.
Reaction SMILES: [C:1](/[C:3](=[C:9]1/[CH2:10][CH2:11][C:12]2[C:17]/1=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)/C(OCC)=O)#[N:2].[C-:19]#[N:20].[K+]>C(O)C.O>[C:1]([CH2:3][C:9]1([C:19]#[N:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)#[N:2]
Reactant: CCOC(=O)/C(C#N)=C1\CCc2ccc(F)cc21
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC1(C#N)CCc2ccc(F)cc21
Temperature: 65 °C
Reaction time: 7 h

Procedure:
To a solution of (E)-ethyl 2-cyano-2-(6-fluoro-2,3-dihydro-1H-inden-1-ylidene)acetate (Prep44, 7.5 g, 0.03 mol) in ethanol (100 ml), a solution of KCN (4.65 g, 0.08 mol) in water (30 ml) was added. The mixture was warmed to 65° C., and stirred for 7 h.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[O:8]([CH2:15][CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][C:19]=1[NH2:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:28][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[NH:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:6]
Reactant: Nc1cnc2ccccc2c1NCCOc1ccccc1
Reactant: COCCC(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: COCCC(=O)Nc1cnc2ccccc2c1NCCOc1ccccc1
Yield: 110.2 %

Procedure:
3-methoxypropanoyl chloride (0.86 ml, 7.9 mmol) was added dropwise over a 30 minute period to a chilled (ice bath) solution of N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol) in dichloromethane (100 ml). After a few hours, a precipitate formed. The solvent volume was reduced under vacuum to near dryness and hexane (100 ml) was added. Vacuum filtration provided 2.9 g of 3-methoxy—N-{4-[(2-phenoxyethyl)amino]quinolin-3-yl}propanamide as a hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CNc1nc(C#N)nc2ccc(OCc3ccccn3)cc12

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23 mmol), 2-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesium carbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 160° C., Rf=0.4 (CH2Cl2/MeOH=15:1) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].P(Cl)(Cl)(Cl)(Cl)[Cl:16].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:16])=[O:7]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc(C(=O)Cl)c1[N+](=O)[O-]

Procedure:
Reaction of 30 g of 3-methoxy-2-nitrobenzoic acid and 31.6 g of phosphorus pentachloride in 400 ml of methylene chloride at reflux for 2 hours followed by treatment of the crude product obtained with toluene 3 times gave 3-methoxy-2-nitrobenzoyl chloride as a solid. A solution of 30 g of this acid chloride in 50 ml of tetrahydrofuran was added to a solution of 28.7 g of 5-aminotetrazole monohydrate in 300 ml of tetrahydrofuran and 15 ml of water. A white precipitate appeared immediately but the mixture was allowed to stand for 3 hours. It was then diluted with water and the white solid was separated by filtration and air dried to give 3-methoxy-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 271° C. after recrystallization from dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:7]([C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[C:10]([F:13])([F:12])[F:11])=[O:9])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: Cc1nc(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)c(C(F)(F)F)o1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-methyl-5-trifluoromethyloxazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (58% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.98, 6.99, 3.75-3.95, 3.50-3.59, 2.55, 1.51, 0.71-0.80, 0.45-0.49, 0.06-0.12. MS (ES+) m/z 453 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[O:11][C:10](=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:20].CN1CCOCC1>CN(C)C=O>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][NH:17][C:12]([CH2:13][N:8]([CH2:9][C:10]([OH:11])=[O:15])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])=[CH:26][CH:25]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)OC(=O)C1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)NCC(=O)c1ccc(Br)cc1
Yield: 80.2 %

Procedure:
2,6-Dioxo-morpholine-4-carboxylic acid tert-butyl ester (2.5 g, 11.6 mmol) was added to a solution of 2-amino-1-(4-bromo-phenyl)-ethanone hydrochloride (3.05 g, 12.2 mmol) and 4-methylmorpholine (1.92 mL, 17.4 mmol) in dimethylformamide (15 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and washed with water (50 mL), aqueous hydrogen chloride (0.5 N, 2×50 mL), and saturated sodium bicarbonate (2×50 mL). The basic extracts were neutralized and extracted with ethyl acetate (2×75 mL). The combined organic phases from the second extraction were dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to provide ({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetic acid (4 g, 9.3 mmol, 80%). C17H21BrN2O6 calculated 428.0 observed [M+1]+431.1; rt=2.36 min.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][C:55]1[N:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1)[CH3:47]>CN(C)C=O>[CH2:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][C:55]1[N:60]=[CH:59][C:58]([NH:61][C:11](=[O:13])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[CH3:14])=[CH:57][CH:56]=1)[CH3:47]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CCc1ccccc1Oc1ccc(N)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.7 %

Procedure:
In a 8 mL vial N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (208 mg, 1.022 mmol) was dissolved in N,N-dimethylformamide (4 mL) to give a colourless solution. N-ethyl-N-(1-methylethyl)-2-propanamine (0.223 mL, 1.277 mmol) and N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate (328 mg, 1.022 mmol) were added. The reaction mixture was stirred at room temperature for 15 min. 6-[(2-ethylphenyl)oxy]-3-pyridinamine (Intermediate 46, 228 mg) was added and the reaction mixture was warmed to 60° C. After 24 hours, additional 150 mg of N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate were added. After additional 8 hours, the solvent was evaporated under vacuum using the Genevac affording a dark brown oil which was purified by silica gel chromatography (Biotage system, 25 g SNAP column) with as eluent a gradient Cyclohexane/EtOAc from 3:1 to 1:1 in 10 CV, then 1:1 for 5 CV. The collected fractions afforded the title compound as a pale orange solid (88.6 mg).
Reaction SMILES: [C:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH2:2][CH2:3][CH3:4].[ClH:19].[H][H].CC(C)=O>O1CCOCC1.[Pd]>[ClH:19].[C:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCCC(=O)Oc1ccc(N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
10 g of 2-butanoyloxy-5-nitro-benzoic acid, 8.5 ml of dioxane, 1.5 ml of HCl 4M solution in dioxane and 1.0 g of Pd/C at 5% were loaded into a 300 ml reactor at 16±2° C. After two vacuum-nitrogen cycles, the reactor was saturated with hydrogen at 10 bar and kept at 16±2° C. for 6 hours. At the end, nitrogen atmosphere was restored in the reactor and the reaction mixture was added with 125 ml of acetone at 25° C. The suspension was stirred at 25° C. for 30 minutes to obtain the dissolution of the undissolved product and the carbon suspension was filtered on a celite panel which was then washed with 60 ml of acetone. The resultant solution was then evaporated under vacuum at 30° C. and the solid residue was dried under vacuum at 35° C. for 4 hours to obtain 10 g of the expected product (99% yield).
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6].[N+:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].Cl>O.C(OCC)C>[N+:11]([C:14]1[CH:15]=[C:16]([S:20]([N:3]2[CH2:10][CH2:9][CH2:8][C@H:4]2[C:5]([OH:7])=[O:6])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 15 °C
Yield: 81 %

Procedure:
To a solution of 12.0 g of sodium hydroxide in 150 ml of water was added 15.0 g of L-proline and dissolved under water-cooling at 15° C. The solution was stirred under water-cooling at 15° C. and to the reaction mixture was added 30.0 g of 3-nitrobenzenesulfonyl chloride and 15 ml of diethyl ether under stirring for 15 minutes. After stirring at room temperature for 80 minutes, the reaction mixture was acidified at pH2 with concentrated hydrochloric acid and the separated oily substance was extracted with ethyl acetate. After the organic layer was washed with aqueous sodium chloride, the solution was filtered and the filtrate was concentrated under reduced pressure. The crystallized residue was boiled with 300 ml of hexane-ethyl acetate (1:1) and was cooled. The obtained crystals were collected by filtration to give 31.7 g of N-3-nitrobenzenesulfonyl-L-proline, melting at 155°-157° C., [α]23D =-71.3° (c=1, CHCl3)
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1O
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1cccc(F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of methyl salicylate (1.512 g, 9.93 mmol) in N,N-dimethylformamide (15 ml) were added 3-fluorobenzyl bromide (1.3 ml, 10.6 mmol) and potassium carbonate (1.780 g, 12.88 mmol), and the mixture was stirred at 80° C. for 5 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-(3-fluorobenzyloxy)benzoate (1.991 g, 7.65 mmol, yield 77%). This was dissolved in methanol (15 ml), 1N-aqueous sodium hydroxide solution (15 ml) was added at room temperature, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 2-(3-fluorobenzyloxy)benzoic acid (1.790 g, 7.27 mmol, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[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][CH2:26][NH:27][CH2:28][CH:29]3[CH2:33][CH2:32][C:31](=[O:34])[O:30]3)[N:9]=2)[CH:7]=1.C=O.[BH3-][C:42]#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[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][CH2:26][N:27]([CH3:42])[CH2:28][CH:29]3[CH2:33][CH2:32][C:31](=[O:34])[O:30]3)[N:9]=2)[CH:7]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCC(CNCCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)O1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)CC1CCC(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (140 mg, 0.26 mmol) in MeOH (20 mL) was added 37% formaldehyde in water (23 mg), followed by NaBH3CN (24.6 mg, 0.39 mmol). The resulting solution was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min); Detector, 254/220. This resulted in 22.4 mg of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[methyl[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 28) [M+H]+=560.2, RT=0.94 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.38 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 4.59-4.55 (m, 1H), 4.30-4.27 (m, 2H), 2.94-2.88 (m, 2H), 2.62 (d, 2H, J=5.6 Hz), 2.44-2.41 (m, 2H), 2.32 (s, 3H), 2.14-2.11 (m, 1H), 1.83-1.77 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26].O>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:26]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1cc([N+](=O)[O-])ccc1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-hydroxy-4-nitrobenzoate (500 mg) obtained in Step A of Example 139 in acetone (5.0 mL) were added potassium carbonate (580 mg) and iodoethane (340 μL), and the mixture was stirred overnight with heating under reflux. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (550 mg).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH3:20]>>[CH3:13][C:12]1[O:11][CH2:10][N:18]([C:19]([CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH3:20])[C:8](=[O:16])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=NC(C)(C)c1cccc(Cl)c1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cccc(Cl)c2)CO1
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (1.0 g) and N-methylene-1-methyl-1-(3-chlorophenyl)ethylamine (Compound of Example 3) (0.76 g) was heated at 15 0° C. for 30 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (1.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].N([O-])=[O:13].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:13])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 5 °C
Yield: 91.2 %

Procedure:
p-Cyanobenzamide (14.6 g), sodium nitrite (20.7 g), acetic acid (200 ml), and acetic anhydride (20 ml) were mixed and stirred vigorously at 5° C. To the mixture, trifuloroacetic acid (35 g) was added dropwise over three hours, and further stirred vigorously for five hours. The solvent was removed under reduced pressure, and water (300 ml) was added to the residue. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 13.4 g of p-cyanobenzoic acid (yield 92%). The p-cyanobenzoic acid obtained had a purity of 98%.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][CH:6]([C:11]([O:13]C)=O)[C:7](OC)=[O:8].C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].Cl>CO>[OH:13][C:11]1[C:6]([O:5][CH3:4])=[C:7]([OH:8])[N:21]=[CH:19][N:20]=1
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(O)ncnc1O
Temperature: 0 °C

Procedure:
A modified procedure of Bretschneider, Richter, and Klotzer, Monatsh. Chem. 96(6), 1661-76 (1965), was used. Absolute methanol (1.0 L) was added with ice bath cooling to sodium methoxide (175 g, 3.24 moles) in a 3 L round bottom flask. When the mixture had cooled to less than 20° C., dimethyl methoxymalonate (162.14 g, 1.00 mole) was added, and then solid formamidine acetate (104.11 g, 1.00 mole) was added. The mixture was stirred i the ice bath for 30 minutes, and then refluxed for 1 hour. The mixture was cooled in a cold water bath and then concentrated HCl (about 350 mL) was added until the mixture was strongly acidic on pH test paper. The precipitate was filtered, suspended in cold water (about 400 mL), and then filtered again. The white powder was dried in vacuo (125.84 g, 88.7%), and carried on without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[C:14](=[O:15])[O:13][C:12]([CH3:17])([CH3:16])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[C:19]([Mg]Br)([CH3:21])=[CH2:20].OC1C=C(C(C2C(=O)OC(C)(C)OC2=O)CC=C)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:9]2[C:10](=[O:18])[O:11][C:12]([CH3:16])([CH3:17])[O:13][C:14]2=[O:15])[C:19]([CH3:21])=[CH2:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Reactant: C=C(C)[Mg]Br
Agent: C=CCC(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Product: C=C(C)C(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Yield: 37.4 %

Procedure:
Compound 8.1 (2.00 g, 8.1 mmol) was treated with isopropenylmagnesium bromide (available from Aldrich) (0.5 M in THF) (97 mL, 48 mmol) according to the method described for preparation of 43.1 to afford 48.1 (0.88 g, 38%) as a yellow oil.