Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[N:13][C:12]=3[CH:16]=2)[CH2:7][CH2:6]1)=[O:4].O>CCS>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:16][C:12]=2[N:13]=[CH:14]1
Reactant: COC(=O)C1(c2ccc3ocnc3c2)CC1
Solvent: O
Solvent: CCS
Product: O=C(O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of crude 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 mL) was added A1Cl3 (5.3 g, 40.1 mmol) in portions at 0° C. The reaction mixture was stirred for 18 hours at room temperature. Water (20 mL) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/EtOAc 1:2) to give 1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280 mg, two steps: 11%). 1H NMR (DMSO, 400 MHz) δ 12.25 (brs, 1H), 8.71 (s, 1H), 7.70-7.64 (m, 2H), 7.40 (dd, J=1.6, 8.4 Hz, 1H), 1.49-1.46 (m, 2H), 1.21-1.18 (m, 2H). MS (ESI) m/e (M+H+) 204.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]([C:17]([OH:19])=O)=[CH:15][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[N:13]2)=[O:10])=[N:6][CH:7]=1.Cl.[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:31])[CH3:30].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:17]([C:16]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[N:13]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)=[O:19])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COCCOCCOc1cc(C(=O)O)n(CC(=O)Nc2ccc(Cl)cn2)n1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOc1cc(C(=O)NC2CCN(C(C)C)CC2)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 16 h

Procedure:
To 310 mg 2-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxy]-2H-pyrazole-3-carboxylic acid in 5 ml DCM and 0.3 ml NEt3, 110 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 197 mg BOP-CL were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:5][CH:4]1[C:6]([OH:8])=O.Cl.[NH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([NH:26][C:27]([C:29]4[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=4)=[O:28])[CH:25]=3)=[N:15][N:14]2[CH:37]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][CH:3]1[CH2:5][CH:4]1[C:6]([NH:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([NH:26][C:27]([C:29]4[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=4)=[O:28])[CH:25]=3)=[N:15][N:14]2[CH:37]=1)=[O:8]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: COC1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CC1C(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 35.6 %

Procedure:
In the same manner as in Example 278 and using 2-methoxycyclopropanecarboxylic acid (86 mg, 0.74 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.49 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (280 mg, 0.74 mmol), N,N-diisopropylethylamine (190 mg, 1.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (83 mg, 35%) was obtained as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][N:13]([CH3:30])[C:14](=[O:29])/[CH:15]=[CH:16]/[C:17]1[CH:18]=[N:19][C:20]([NH:23][CH2:24][C:25]([O:27]C)=O)=[CH:21][CH:22]=1.COC([CH2:35][NH:36]C1N=CC(/C=C/C(N(C)CC2C3C(=CC=CC=3)NC=2C)=O)=CC=1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][N:13]([CH3:30])[C:14](=[O:29])/[CH:15]=[CH:16]/[C:17]1[CH:18]=[N:19][C:20]([NH:23][CH2:24][C:25]([NH:36][CH3:35])=[O:27])=[CH:21][CH:22]=1
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2cn(C)c3c(Cl)cccc23)cn1
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Product: CNC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2cn(C)c3c(Cl)cccc23)cn1
Yield: 94 %

Procedure:
According to the procedure of Example 21, except substituting (E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide (0.75 g, 1.8 mmole) for the (E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide, the title compound (0.721 g, 94%) was prepared as a white solid: MS (ES) m/e 426.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH3:15][Mg+].[Br-]>C1COCC1>[C:12]([C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:13])[CH3:15]
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Reaction time: 0.75 h
Yield: 44.5 %

Procedure:
To a solution of 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride (0.50 g, 2.0 mmol) in THF at -78° C. under N2 was added MeMgBr (0.75 ml, 2.3 mmol). The reaction was stirred 0.75 h, quenched with H2O (1 ml) and diluted with EtOAc (30 ml). The organic layer was washed with H2O, brine and then dried over MgSO4. The residue was chromatographed (SiO2, hexanes/EtOAc, 2:1) to provide the 5-acetyl-2-chloro-4-trifiuoromethylpyrimidine (0.20 g) in 43% yield. The title compound was then prepared as described for ethyl 2-[N-(1'-aminocitraconamide)]-4-trifluoromethylpyrimidine-5-carboxylate of Example 20, resulting in a 29% yield (0.08 g); m.p. 61-62° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@@H:5]1[CH2:7][C@@H:6]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][C:23]=1[F:30]>CN(C=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:3][CH2:4][C@@H:5]2[CH2:7][C@@H:6]2[CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:24][C:23]=1[F:30]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(Br)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Sodium hydride (235 mg, 5.87 mmol) was added to a stirring solution of tert-butyl 4-((1R,2R)-2-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (Intermediate 4, 1 g, 3.92 mmol) in DMF (10 mL) that had been cooled to 0° C. in an ice bath and placed under an inert atmosphere. 10 min later 1-bromo-4-(bromomethyl)-2-fluorobenzene (Step B product of Intermediate 13, 1.1 g, 4.11 mmol) was introduced to the mixture. The ice bath was removed and the reaction warmed to rt. The reaction was aged for 1 hr then diluted with EtOAc (20 mL) and neutralized by the slow addition of saturated aqueous ammonium chloride solution (20 mL). The layers were cut and the aqueous phase extracted with EtOAc (20 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto a silica column (KP-Sil 50 g SNAP column, Biotage system) eluting with a range of 0-20% EtOAc/Hex over 12 CV to give the desired compound (1.73 g, 91%). LC/MS (m/z): 442 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:36])=O>COC(C)(C)C>[Cl:36][C:15]1[N:14]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: COc1cc(-c2cc3ncccc3cn2)cc(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)c1ccccc1
Product: COc1cc(-c2cc3ncccc3c(Cl)n2)cc(OC)c1OC

Procedure:
565 mg 7-(3,4,5-Trimethoxy-phenyl)-[1,6]-naphthyridine (5.2) and 15 μL N,N-diethylaniline were stirred into 4 mL phosphorus oxychloride overnight at 100° C. and at ambient temperature over 2 days. The reaction mixture was evaporated down, and a small amount of ethyl acetate was added. Upon scratching a precipitate were formed. Methyl-tert-butylether was added and the precipitate was isolated and dried overnight at 50° C. under vacuo.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:16]=[C:17]([CH3:19])[N:18]=2)[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:27])C(=O)C1>CC#N.CCOC(C)=O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:16]([I:27])=[C:17]([CH3:19])[N:18]=2)[N:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(CC)c1cc(C(F)(F)F)nn2cc(C)nc12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C(F)(F)F)nn2c(I)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 8-(1-ethyl-propyl)-2-methyl-6-trifluoromethyl-imidazo[1,2-b]pyridazine (0.18 g, 0.67 mmol) in CH3CN (5 mL) is treated with NIS (0.18 g, 0.80 mmol), and stirred at rt overnight. It is diluted with EtOAc (50 mL), washed with 5% Na2SO3 (2×25 mL); dried (Na2SO4), filtered and concentrated to give the title compound (0.26 g, 0.65 mmol, 98%). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 6H), 1.79-1.92 (m, 4H), 2.59 (s, 3H), 3.30-3.43 (m, 1H), 7.09 (s, 1H). ES-MS (m/z): calcd for C13H15F31N3 (M+H)+: 398.2. found: 398.1.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:45])[C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=1)[C:28]#[N:29].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:26]=[C:25]([Cl:24])[C:32]([O:33][C:34]3[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=3)=[C:31]([Cl:45])[CH:30]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: N#Cc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 3,5-dichloro-4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.00 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Br:13])[CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1cc(N)cc(Br)c1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a stirred solution of ethyl 3-amino-5-bromobenzoate (2 g, 8.73 mmol) and cyclopentanone (2.2 g, 26.1 mmol) in methanol (20 mL), acetic acid (1.04 g, 17.4 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (1.37 g, 21.83 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford desired compound (1.6 g, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12](O)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:31]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12]([Cl:31])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)C(F)(F)C3
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Cl)C(F)(F)C3
Temperature: 70 °C

Procedure:
To a stirred solution of the product from step (a) (25 mg) in SOCl2 (1 ml) was added pyridine (1 ml). The mixture was heated to 70° C. for 30 minutes after which LCMS indicates no starting material. The volatiles were evaporated in vacuo. The residue was dissolved in EtOAc and washed with 1 M citric acid, saturated NaHCO3, brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-titled compound (21 mg) as a colorless oil which was used as obtained in the next step. MS: ESI (positive): 330 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCBr
Yield: 3476.4 %

Procedure:
This example is a method of synthesis for inventive compound no. 3549 (see above for chemical name and structure). A solution of 11-bromoundecanoic acid (5.70 g, 22 mmol, available from Aldrich) and p-toluenesulfonic acid (0.1 g) in absolute ethanol (100 ml) was refluxed for 3 hours. A saturated aqueous sodium bicarbonate solution (40 ml) was added and the reaction mixture then extracted with three 70 ml aliquots of dichloromethane. The combined extracts were washed with water (50 ml) and saturated aqueous salt solution (50 ml) and the solvent was evaporated, leaving a colorless oil. Ethyl 11-bromoundecanoate (5.92 g, 94% yield) was collected during distillation (2 mm) at 135° C. A solution of this bromoester (5.92 g, 20 mmol) and 1-sodiotheobromine (4.08 g, 20 mmol) in dimethylsulfoxide (80 ml) was stirred for 18 hours at ambient temperature. The mixture was added to water (100 ml) and dichloromethane (100 ml). The aqueous layer was extracted with two 80 ml aliquots of dichloromethane. The combined organic layers were washed with water (80 ml) and saturated aqueous salt solution (80 ml), dried over magnesium sulfate, and the solvent was evaporated under vacuum, leaving a white solid residue. The residue was recrystallized in dichloromethane/ether/hexane, yielding 4.95 g of 1-(ethyl 11-yl-undecanoate)-3,7-dimethylxanthine (62% yield).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[OH:7][CH2:8][C:9](O)=O>O>[NH2:6][N:5]1[C:3]([SH:4])=[N:2][N:1]=[C:9]1[CH2:8][OH:7]
Reactant: NNC(=S)NN
Reactant: O=C(O)CO
Solvent: O
Product: Nn1c(S)nnc1CO
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
A mixture of 10.6 g (0.1 mole) of thiocarbohydrazide and 25.0 g (0.33 mole) of hydroxyacetic acid are heated and stirred at 130° C. for 20 minutes. The mixture is cooled to room temperature and diluted with 25 ml of water. It is then cooled for 24 hours at 11° C., yielding 7.0 g of crystals. The latter are recrystallized from chloroform/methanol, affording 4.5 g of solvated product. The product is dried in vacuo, affording 2.0 g of pale yellow crystals of 4-amino-5-mercapto-4H-1,2,4-triazole-3-methanol. m.p. 150.5°-151.5° C. When the reaction is repeated, using a longer heating time, (1 hour at 125° C.), and is followed by recrystallization from methanol/water, a higher yield of the same product is obtained (80%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[I-].[K+]>C(#N)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH3:20]
Reactant: O=Cc1ncc[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1ccnc1C=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 1H-imidazole-2-carbaldehyde (4.47 g) in acetonitrile (80 ml) were added potassium carbonate (12.93 g), ethyl bromoacetate (6.2 ml) and potassium iodide (7.78 g) at room temperature. The mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, the mixture was filtered to remove the precipitates. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using dichloromethane and methanol (99:1 to 96:4) as eluents to afford the title compound (5.23 g, yield: 62%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:21][Mg]Br.C1COCC1>>[OH:17][C@:14]1([CH3:21])[C:13]([CH3:19])([CH3:18])[C:12](=[O:20])[N:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=2)[C@@H:15]1[CH3:16]
Reactant: COc1cc(N2C(=O)C(C)(C)C(=O)C2C)ccc1C#N
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(N2C(=O)C(C)(C)[C@@](C)(O)[C@H]2C)ccc1C#N

Procedure:
Using 2-methoxy-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (100 mg) and methylmagnesium bromide-THF solution (3.67 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless solid (yield: 96 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][C:15]2[CH:16]=[C:17]3[C:21]4=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]4[C@H:19]4[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]34)[CH:23]=2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Product: Fc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C(F)(F)F)c1

Procedure:
Using 4-fluoro-2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H—[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 131. 1H NMR(CDCl3) δ 7.61 (dd, 1H, J=8.4, 5.5 Hz), 7.40 (dd, 1H, J=8.8, 2.8 Hz), 7.19 (td, 1H, J=8.3, 2.6 Hz), 6.35 (d, 1H, J=2.2 Hz), 6.19 (d, 1H, J=2.2 Hz), 4.56 (ABq, 2H, JAB=14.3 Hz), 4.44 (s, 2H), 4.22 (app d, 1H, J=12.8 Hz), 3.92 (broad s, 1H), 3.71 (app t, 1H), 3.38-3.28 (m, 2H), 3.22-3.02 (m, 4H), 2.65 (app t, 1H), 2.53 (app t, 1H), 2.10-2.00 (m, 2H). LRMS (ES)+: 422.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:19]([CH3:30])[C:20]([C:28]#[N:29])=[C:21]2[C:25]=1[O:24][C:23]([CH2:26][OH:27])=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:19]([CH3:30])[C:20]([C:28]#[N:29])=[C:21]3[C:25]=2[O:24][C:23]([CH2:26][OH:27])=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(CO)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(CO)nc2c1C#N
Temperature: 95 °C
Reaction time: 3 h
Yield: 11.1 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (18.2 μl, 0.143 mmol) and triethylamine (26.7 μl, 0.191 mmol) were added to a dimethyl sulfoxide (0.5 ml) solution of 7-fluoro-2-hydroxymethyl-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-218) (27.0 mg, 0.096 mmol), followed by stirring in an oil bath at 95° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (10 ml), and washed with saturated brine (10 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol-10:1), and the eluate was purified in slurry with diethyl ether to obtain the entitled compound (4.00 mg, 11.1%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:25]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: Cc1occc1C(=O)O
Product: Cc1occc1C(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 99.1 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11 mg (0.087 mMol) 2-methylfuran-3-carboxylic acid, 12.7 mg (99%) of the title compound were recovered as a beige solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]3[C:22]([O:28]C)=[N:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[N:12][C:11]=12)=[O:6].O1CCOCC1.Cl>>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]3[C:22](=[O:28])[NH:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[N:12][C:11]=12)=[O:6]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCCl)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Reaction time: 1.5 h

Procedure:
Prepared by the method described in Example 202, replacing (R)—N-tert-butyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with (R)—N-(2-chloro ethyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 163, 100 mg, 0.239 mmol), replacing 2 M HCl with 4 M HCl dioxane solution, and reaction was conducted at 100° C. for 90 minutes. LCMS (apci) m/z=405.0 (M+H).
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[C:24]([CH3:25])=[CH:23][C:22](O)=[CH:21][C:20]=2[CH3:27])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:25][C:24]1[CH:23]=[C:22]([O:5][C@@H:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[CH:21]=[C:20]([CH3:27])[C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][OH:11])[CH:14]=1
Reactant: CS(=O)(=O)O[C@H]1CCOC1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
The crude (S)-tetrahydrofuran-3-yl methanesulfonate 2b (522 mg, 3.14 mmol), 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (714 mg, 3.13 mmol, prepared by a method disclosed in Chinese patent application CN101616913) and cesium carbonate (3.10 g, 9.39 mmol) were dissolved in 30 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-(2′, 6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 2c (540 mg, yield 58.0%) as a colorless oil.