Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].O[CH2:14][NH:15][C:16](=[O:19])[CH2:17][Cl:18]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:10]=[C:9]([CH2:14][NH:15][C:16](=[O:19])[CH2:17][Cl:18])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: Cc1ccc(O)c2c1CCC2=O
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Product: Cc1cc(CNC(=O)CCl)c(O)c2c1CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
9.3 Grams of 4-methyl-7-hydroxy-1-indanone and 30 g of N-hydroxymethyl-α-chloroacetamide were dissolved by adding 280 ml of concentrated sulfuric acid under a cooling condition. After the mixture was allowed to stand overnight, the mixture was poured into ice-water. The crystals formed in the mixture were collected by filtration and were recrystallized from ethanol to obtain 49 g of 4-methyl-6-α-chloroacetylaminomethyl-7-hydroxy-1-indanone.
Reaction SMILES: [N:1]([C:4]1(Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)=[C:2]=[S:3].[ClH:11].[CH:12]([NH2:14])=[NH:13].[OH-].[Na+]>C1COCC1>[NH2:13][CH:12]=[N:14][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:11])=[CH:6][CH:5]=1)=[S:3]
Reactant: S=C=NC1(Cl)C=CC=CC1
Reactant: Cl
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC=NC(=S)Nc1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A mixture of 10 g (51.2 mmol) 4-isothiocyanato-4-chloro benzene in 51 ml THF at 0° C. was treated with 5.15 g (64.02 mmol) formamidine hydrochloride and 64 ml 1N NaOH and allowed to stirr for 5 h after which the mixture was concentrated. 500 ml ethyl acetate and 100 ml water was added and the precipitate was filtered off, washed with water and dried to yield the intermediate 1-[1-Amino-methylidene]-3-(4-chloro-phenyl)-thiourea (MH+ 213.5) which was used without further purification. The thiourea was taken up in 50 ml THF and treated with 8.55 g (51.2 mmol) ethyl bromoacetate and 15.3 ml NEt3 and stirred at 50° C. for 18 h. The mixture was concentrated and extracted with CHCl3. The organic layer was washed with aqueous Na2CO3 (1M) and saturated NaCl solution, dried with MgSO4 and evaporated. The residue was purified with column chromatography on silica to yield 3.48 g (22%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.CN1CCOCC1.Cl.[CH3:26][O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH2:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C@@H:29]([CH2:31][CH2:32][S:33][CH3:34])[C:28]([O:27][CH3:26])=[O:35])=[O:8])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1-c1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(O)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of 4-hydroxy-2-(4-fluorophenyl)benzoic acid (4.5 g; 0.019 mol) in DMF (90 ml) cooled to 0° C. under an argon atmosphere was added in sequence NMM (6.4 ml; 0.058 mol), L-methionine methyl ester hydrochloride (4.0 g; 0.020 mol), EDC (4.47 g; 0.023 mol) and HOBT (2.7 g; 0.020 mol) and the reaction warmed to ambient temperature and stirred for 3 hours. The DMF was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine, filtered through PSI filter paper and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography eluting with ethyl acetate/iso-hexane (1:1) gave methyl (2S)-2-[4-hydroxy-2-(4-fluorophenyl)benzoylamino]-4-methylsulfanylbutyrate as a white foam (5.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1)=[O:33]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(F)c(OCc2ccccc2)c(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(F)c2OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 2-(benzyloxy)-1-bromo-3,5-difluorobenzene (13.7 g, 46 mmol) in anhydrous THF (100 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (18.4 mL, 46 mmol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (10.43 g, 38.3 mmol) in anhydrous THF (40 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:20→1:10) to provide (R)-tert-butyl 3-(2-(benzyloxy)-3,5-difluorobenzoyl)piperidine-1-carboxylate (6.4 g, 32%) as a light yellow oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:11]=[CH:10][C:9]([S:12][C:13]#N)=[CH:8][C:5]=1[C:6]#[N:7].[BH4-].[Na+].S(OC)(OC)(=O)=O>O.CO>[NH2:3][C:4]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#CSc1ccc(N)c(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: COS(=O)(=O)OC
Product: CSc1ccc(N)c(C#N)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Sodium hydroxide (97%, 1.20 g (29.1 mmol)) was dissolved in a mixed solvent of water (4.0 ml) and methanol (20.0 ml). To this, 2-amino-5-thiocyanobenzonitrile (5.03 g (28.7 mmol) was added with stirring. To the resulting mixture, after 30 minutes' stirring under cooling with ice, sodium borohydride (90%, 0.60 g (14.3 mmol)) was added and further stirred for 30 minutes under cooling with ice. Then, dimethyl sulfate (95%, 3.0 ml (30.0 mmol)) was added dropwise. The resulting mixture was further stirred under cooling with ice for 30 minutes and at room temperature for 30 minutes, and then concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 4.73 g (100%) of 2-amino-5-methylthiobenzonitrile as yellow crystals.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:8]1[C:9]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:10]=2[S:11][C:12]=1[C:13](Cl)=[O:14].[OH2:22]>O1CCCC1.CO.[OH-].[Na+]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:9]2[C:8]([O:4][CH:1]([CH3:3])[CH3:2])=[C:12]([C:13]([OH:22])=[O:14])[S:11][C:10]=2[CH:16]=1
Reactant: COc1ccc2c(Cl)c(C(=O)Cl)sc2c1
Reactant: O
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(OC(C)C)c(C(=O)O)sc2c1

Procedure:
Isopropanol (16.8 g, 280 mmoles) is added dropwise to a stirred suspension of sodium hydride (11.2 g of a 60% dispersion in mineral oil, 280 mmoles) in tetrahydrofuran (50 mls) under argon. After 20 minutes a solution of 3-chloro-6-methoxybenzo-[b]thiophene-2-carbonyl chloride (24.2 g, 93 mmoles) in warm tetrahydrofuran (180 mls) is added gradually during 5 minutes, and the mixture is heated under reflux. After 16 hours the mixture is cooled and stripped of solvent under reduced pressure. The residue is partitioned between water (600 mls) and ether (300 mls). The layers are separated and the aqueous phase extracted twice with ether (200 mls). The combined ether extracts are washed with saturated brine, dried over MgSO4, and stripped of solvent under reduced pressure to leave the crude ester as a syrup which also contains mineral oil. The syrup is stirred in a mixture of methanol (20 mls) and 1N sodium hydroxide (100 mls), and heated under reflux. After 12 hours the mixture is stirred into water (600 mls) and extracted twice with ether (150 mls). The aqueous solution is stirred and acidified with concentrated HCl, and the resulting precipitate is filtered off, rinsed well with water, and dried to afford the product (11.7 g): m=155°-156° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:35](CC)[C:36]([O-:38])=[O:37].[CH3:41][C:42](C)=O>>[CH2:41]([O:38][C:36](=[O:37])[CH2:35][O:15][C:12]1[CH:11]=[CH:10][C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1)[CH3:42]
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Reactant: CCC(Br)C(=O)[O-]
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1
Temperature: 25 °C

Procedure:
Material from Example 5 (0.200 g, 0.536 mmol) was suspended in acetone to which K2CO3 was added. This was treated with bromo-ethyl-acetate (0.089 g, 0.536 mmol) at which time the reaction mixture was heated to reflux for 4 hrs. Reaction mixture cooled to room temperature, solid filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (24 mg, 10%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.22 (t, J=6.99 Hz, 3H), 2.34 (s, 3H), 2.74 (s, 3H), 4.20 (q, J=6.99 Hz, 2H), 5.47 (s, 2H), 6.49 (d, J=7.72 Hz, 1H), 6.75 (d, J=8.82 Hz, 2H), 7.00 (d, J=8.09 Hz, 1H), 7.20 (d, J=8.46 Hz, 2H), 7.25-7.40 (m, 2H), 7.87 (d, J=8.82 Hz, 1H), 8.63 (d, J=7.72 Hz, 1H), 9.06 (d, J=8.46 Hz, 1H), 9.89 (s, 1H); MS(ESI) m/z 460 (M+H)+, (ESI−) m/z 458 (M−H)−.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([CH3:12])[CH2:10][OH:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:46]=[CH:45][C:44](F)=[CH:43][CH:42]=3)[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>CS(C)=O>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:40](=[O:48])[C:41]3[CH:42]=[CH:43][C:44]([N:6]4[CH2:7][CH2:8][N:3]([CH:9]([CH3:12])[CH2:10][OH:11])[CH2:4][CH2:5]4)=[CH:45][CH:46]=3)[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3ccc(F)cc3)[nH]n2)cc(OC)c1
Reactant: CC(CO)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)CO)CC4)cc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
2-(Piperazin-1-yl)propan-1-ol 2HCl (0.274 g, 1.26 mmol) was added to N-ethyl-N-propan-2-ylpropan-2-amine (0.330 mL, 1.89 mmol) in DMSO (5 mL). The reaction mixture was stirred at room temperature for 10 mins. N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide (0.233 g, 0.63 mmol) was added and the mixture heated at 110° C. for 18 h under nitrogen. Heating was continued for 12 additional days. The reaction was cooled and the crude mixture was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.048 g, 15.44%) as a cream solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH:22]=[CH:23][C:24]([O:26]C)=[O:25])=[CH:16]2)=[O:11].C(O)C.[OH-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:16]2)=[O:11]
Reactant: COC(=O)C=Cc1cc2cc(NC(=O)c3cc4ccccc4o3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)C=Cc1cc2cc(NC(=O)c3cc4ccccc4o3)ccc2[nH]1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
22 (60 mg, 0.167 mmol) was dissolved in DMF (1.5 mL) and ethanol (3 mL) was added. 3N NaOH solution (1.5 mL) was added and the reaction mixture was stirred overnight. The solvent was removed and water (10 mL) was added. The solution was neutralized using 20% HCl. The resulting precipitate was filtered and washed with water. 53 mg (92% yield) of yellow solid 23 was obtained. mp: 268° C. (dec). 1H NMR (DMSO-d6, ppm): 12.27 (brs, 1 H, COOH), 11.53 (s, 1 H, NH), 10.38 (s, 1 H, NH), 8.07-7.35 (m, 9 H, Ar--H, CH=CH), 6.88 (s, 1 H, Ar--H), 6.48-6.44 (d, 1 H, J=16.2 Hz, CH=CH). Anal. (C20H14N2O4 0.4H2O), C, H, N.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[F:9][C:10]1([F:20])[CH2:12][CH:11]1[C:13](OCCCC)=[O:14].Cl>O1CCCC1.O>[F:9][C:10]1([F:20])[CH2:12][CH:11]1[C:13](=[O:14])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCCCOC(=O)C1CC1(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)C1CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of acetonitrile (0.97 mL, 18.5 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. and treated with n-butyllithium in hexanes (11.7 mL, 19.0 mmol) over 5 minutes. The reaction mixture was stirred for 30 minutes, and then n-butyl 2,2-difluorocyclopropane carboxylate (3.0 g, 16.8 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into water (25 mL) and acidified by addition of 10% aqueous hydrochloric acid. The organic layers were extracted into diethyl ether (3×30 mL), dried (MgSO4) and concentrated to afford crude 3-(2,2-difluorocyclopropyl)-3-oxo-propionitrile (2 g).
Reaction SMILES: N#N.C1(NC2CCCCC2)CCCCC1.[Li]CCCC.[C:21]([O:25][C:26](=[O:28])[CH3:27])([CH3:24])([CH3:23])[CH3:22].Br[C:30]1[CH:31]=[C:32]([C:36]2([CH3:41])[O:40][CH2:39][CH2:38][O:37]2)[CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1.CCCCCC>[C:21]([O:25][C:26](=[O:28])[CH2:27][C:34]1[CH:35]=[CH:30][CH:31]=[C:32]([C:36]2([CH3:41])[O:37][CH2:38][CH2:39][O:40]2)[CH:33]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC1(c2cccc(Br)c2)OCCO1
Reactant: CC(=O)OC(C)(C)C
Agent: C1CCC(NC2CCCCC2)CC1
Agent: N#N
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Cc1cccc(C2(C)OCCO2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a degassed solution of dicyclohexylamine (1.03 mL, 5.18 mmol) in toluene (30 mL) was treated 0° C. with n-BuLi (2.07 mL of a 2.5M solution in hexane, 5.18 mmol) and the reaction was stirred at 0° C. for 30 min. Acetic acid tert-butyl ester (0.59 mL, 4.40 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 50 min. To this solution was added a degassed suspension of 2-(3-bromo-phenyl)-2-methyl-[1,3]dioxolane (972 mg, 4.00 mmol) and {[P(t-Bu)3]PdBr}2 (25 mg, 0.03 mmol) and the reaction mixture was stirred at rt for 5 h. The reaction volume was reduced to half by rotary evaporation. The concentrated solution was washed with sat. aq. NH4Cl (30 mL). A large amount of precipitate formed between the aq. and org. layers. The org. layer was separated, and the aq. layer was washed with ether (5×20 mL). The combined org. layers were dried over MgSO4, filtered, and the solvent was removed under reduced. Purification of the residue by FC (9:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (9:1 hept-EA)=0.26. LC-MS-conditions 02: tR=1.05 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH:39]1([C:42]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:43])[CH2:41][CH2:40]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.48 mmol) in DCM (5 mL) was added triethylamine (1 mL), followed by adding cyclopropanecarbonyl chloride (104.5 mg, 0.96 mmol) at 0° C. The reaction mixture was warmed to rt and stirred for 3 hours, then quenched with water (10 mL). The separated organic layer was added saturated aq. Na2CO3 (10 mL) and EtOH (30 mL). The mixture was stirred at rt for 30 minutes and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=80/1) to give the title compound as a white solid (130 mg, 56%).
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)C1C=CC=CC=1.C(C1C=CC=CN=1)#N.[CH2:27]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C1C=CC=CC=1.B(O)(O)C1C=CC=C(F)C=1>ClCCl.CO>[C:39]1([C:35]2[N:34]=[CH:27][C:38]([C:12]3[NH:8][C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[N:10][CH:11]=3)=[CH:37][N:36]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(Cn2ccnc2-c2ccccc2)cc1
Reactant: c1ccc(Cn2ccnc2-c2ccccn2)cc1
Agent: OB(O)c1cccc(F)c1
Solvent: N#Cc1ccccn1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(-c2ncc(-c3cnc(-c4ccccn4)[nH]3)cn2)cc1

Procedure:
The title compound was prepared by the method described in Example 1, except that 2-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according to Example 8, Step A, except that commercially available 2-cyanopyridine was used instead of 3-fluorobenzonitrile) was used instead of 1-benzyl-2-phenyl-1H-imidazole in Step C; Rf 0.43 with 95:5 v/v dichloromethane-methanol; melting point 262° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.33 (s, 2H), 8.63 (d, 1H), 8.43-8.37 (m, 2H), 8.16 (d, 1H), 8.06 (d, 1H), 7.94 (dt, 1H), 7.54-7.49 (m, 3H), 7.43-7.39 (m, 1H); MS (ESI+) m/z 300.1 (M+1); H-PGDS FPBA IC50: 0.125 μM; H-PGDS inhibitor EIA IC50: 0.053 μM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](=O)[CH3:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]([NH2:23])=[NH:22].C[O-].[Na+].F[C:28](F)(F)C(O)=O>CC#N.O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:18]=[CH:28][N:20]=[C:21]([NH2:23])[N:22]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: O=C(O)C(F)(F)F
Reactant: N=C(N)N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: Nc1nccc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)n1
Temperature: 120 °C
Yield: 3 %

Procedure:
A solution of 1-[3-(4-fluorophenyl)-1H-indazol-5-yl]ethan-1-one (73 mg, 0.29 mmol) in dimethoxy DMF acetal (25 mL) was heated to 90° C. overnight. The solution was then concentrated to an oil under vacuo when methanol (10 mL), guanidine (55 mg, 0.57 mmol), and NaOMe (290 μL of a 2 N solution. 0.58 mmol) was added. The reaction was then heated in a sealed tube to 120° C. overnight. The reaction was then acidified with trifluoroacetic acid then subjected to preparative HPLC (CH3CN/water 0.1% TFA) to recover the final compound (3 mg, 3% yield). 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.78 s, 1H), 8.35 (d, 1H), 8.19 (d, 1H), 8.06 (dd, 2H), 7.72 (d, 1H), 7.53 (d, 1H), 7.38 (t, 2H); ES-MS (m/z) 306 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
Prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a yellow solid (270 mg).
Reaction SMILES: [CH3:1][Mg]Cl.CON(C)[C:7](=[O:18])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[C:10]=1[F:17]>C1COCC1>[F:17][C:10]1[C:11]([F:16])=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[CH2:8][C:7](=[O:18])[CH3:1]
Reactant: CON(C)C(=O)Cc1cc(F)cc(F)c1F
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)Cc1cc(F)cc(F)c1F
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of CeCl3 (11.44 g, 0.045 mol) in THF (350 mL) was degassed for 1 h and heated to 45-50° C. for 5 h. When the solution was cooled to −10-5° C., MeMgCl (19.44 g, 0.26 mol) in THF was added and the mixture was stirred for 1 h at −10-5° C. After amide 43 (30.3 g, 0.13 mol) was charged into the reaction mixture at −10-5° C., the mixture was stirred for 5 h at 10-20° C. After the reaction was complete, the mixture was quenched by 1M HCl, and then partitioned with water and EtOAc. The organic phase was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (2-10% EtOAc/PE) to give 44 (20.8 g, 85% yield). 1H NMR (CDCl3, 400 MHz): δ 6.91-6.78 (m, 1H), 6.69 (dd, 1H), 3.77 (d, 2H), 2.25 (s, 3H); MS (ESI) m/e [M+H]+: 189.05.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.[Br:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Br:33][CH2:34][CH2:35][N:13]1[C:14](=[O:16])[C:15]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)=[N:9][C:10]=2[N:11]([CH3:18])[C:12]1=[O:17]
Reactant: BrCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCBr)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.215 mmol, Intermediate 9) in DMF (3 mL) was added 1,2-dibromoethane (100 mg, 0.532 mmol), followed by potassium carbonate (60 mg, 0.429 mmol). The mixture was stirred at 80° C. overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by recrystallization from ethanol to give 1-(2-bromoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (120 mg, 97.6% yield) as white solid. LCMS retention time 2.103 min; LCMS MH+ 573.