Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]([F:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[CH3:2])=[C:16]([F:21])[CH:15]=1
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: Fc1cc(Cl)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1-c1ccc(Cl)cc1F
Temperature: 85 °C
Yield: 53.7 %

Procedure:
2-Acetylphenylboronic acid (5 g, 30.5 mmol) and 4-chloro-2-fluoroiodobenzene (8.6 g, 33.5 mmol) were dissolved in a toluene/ethanol mixture (6:1, 175 mL). An aqueous solution of potassium carbonate (2 M, 60 mL) and tetrakis(triphenylphosphine)palladium (0) (1.06 g, 0.91 mmol) were added to the solution and the entire mixture was degassed using vacuum and stirring with intermittent nitrogen purge. The mixture was heated at 85° C. with stirring for 14 hours. The mixture was allowed to cool and then water was added. The organic phase was separated from the aqueous phase and the aqueous phase was extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-20% methyl tert-butyl ether in hexane, to afford the desired product (4.07 g, 54%) as a yellow oil;
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].C([O-])([O-])=[O:15].[Na+].[Na+]>>[OH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)c(C(=O)O)c1
Agent: [Na+]
Product: O=C(O)c1ccc(O)c(C(=O)O)c1
Yield: 82 %

Procedure:
The same procedure as described in Example 24 was performed but using 2.45 g (10.0 mmol) of 4-bromoisophthalic acid as the substrate and 2.70 g (25.5 mmol) of Na2CO3 instead of Ca(OH)2. A total of 1.49 g (8.2 mmol, 82% yield) of 4-hydroxyisophthalic acid was collected. The purity was determined by 1H NMR to be 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:7]=[C:6]2[N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][N:29]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([CH3:40])[CH:36]=3)[NH:31][C:30]2=[O:41])[CH2:23][CH2:22]1.[H-].[Na+].[CH3:44]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[N:7]=[C:6]2[N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][N:29]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([CH3:40])[CH:36]=3)[N:31]([CH3:44])[C:30]2=[O:41])[CH2:23][CH2:22]1
Reactant: CI
Reactant: COc1cc2nc(N3CCOCC3)nc(N3CCC(CCn4c(=O)[nH]c5ccc(C)cc5c4=O)CC3)c2cc1OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCOCC3)nc(N3CCC(CCn4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
In 5 ml of dimethylformamide was suspended 350 mg (0.7 mmol) of Compound 29 obtained in Example 29, and 42 mg (1.05 mmol) of 60% sodium hydride and 0.1 ml (1.54 mmol) of methyl iodide were added to the suspension. The mixture was stirred at room temperature for one hour, and then a saturated aqueous solution of ammonium chloride was added thereto to stop the reaction. After extraction with ethyl acetate, the organic layer was washed and dried. The solvent was evaporated under reduced pressure, and the resulting crude crystals were washed with a solvent mixture of ethanol and ether to give 190 mg (yield: 48%) of Compound 30 as white crystals.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]#[N:15])=[N:5][N:4]=1)[NH2:2].C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1>O1CCOCC1>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[N:4]3[N:5]=[C:6]([CH2:13][C:14]#[N:15])[C:7]4[C:12]([C:3]3=[N:1][N:2]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:27][CH:26]=1
Reactant: N#CCc1nnc(NN)c2ccccc12
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc3c4ccccc4c(CC#N)nn23)cc1

Procedure:
A mixture of 4-hydrazino-1-phthalazin-acetonitrile (0.7 g), triethylamine (0.4 g), p-methoxybenzoylchloride (0.68 g), dioxane (10 ml), is heated at reflux for 5 h, then it is cooled, the solvent is evaporated under reduced pressure, the residue is taken up with water, recovered by filtration and crystallized from ethanol/chloroform, yielding 3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazin-6-acetonitrile. M.p. 252°-254° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]([CH:9]=[CH2:10])=[O:8].[BH4-].[Na+]>C1COCC1>[N:1]1([CH2:10][CH2:9][CH:7]([OH:8])[CH3:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C=CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)CCN1CCCC1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
Pyrrolidine (2 ml, 24 mmol), THF (20 ml) and methyl vinylketone (2.5 ml, 31 mmol) were mixed together and stirred overnight. NaBH4 (1.17 g, 31 mmol) was added to the reaction mixture and stirred for 3 hours. The reaction was quenched with water (20 ml) and extracted with TBME (2×20 ml). The combined organic extracts were dried over MgSO4, filtered, washed with TBME and concentrated in vacuo. The crude product was purified by column chromatography, eluting with DCM:MeOH:NH3 (94:5:1), to give the title compound as a pale yellow oil (1.3 g, 38%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:27])[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.Cl[CH2:29]I.C([Zn]CC)C>ClCCCl>[C:12]([O:11][C:9](=[O:10])[C:8]1[CH:16]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([O:18][CH2:19][C:20]2([CH3:27])[CH2:25][CH2:24][C:23]3([CH2:29][CH2:26]3)[CH2:22][CH2:21]2)=[CH:6][C:7]=1[F:17])([CH3:14])([CH3:13])[CH3:15]
Reactant: ClCI
Reactant: C=C1CCC(C)(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1
Agent: CC[Zn]CC
Solvent: ClCCCl
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methyl-4-methylenecyclohexyl)methoxy)benzoate (0.30 g, 0.804 mmol) in 1,2-dichloroethane (2 mL), was added chloroiodomethane (0.21 mL, 2.65 mmol), followed by diethylzinc (1M solution in hexanes, 1.33 mL, 1.33 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then quenched with 1N aqueous hydrochloric acid solution. The aqueous layer was separated and extracted with dichloromethane (3×30 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 5% ethyl acetate in hexanes) afforded the title compound (0.29 g, 93%) as a colorless oil: MS (ES+) m/z 333.2 (M−55).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:23]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:23]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: c1ccc(COCCC[C@@H]2CCNC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC[C@@H](CCCOCc3ccccc3)C2)c1
Temperature: 99 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 3(R)-[3-(benzyloxy)propyl]pyrrolidine (350 mg, 1.60 mmol) and 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (627 mg, 1.76 mmol, 1.1 equiv.) in 10 mL of anhydrous toluene were added successively at room temperature sodium tert-butoxide (307 mg, 3.20 mmol, 2.0 equiv.), tris(dibenzylideneacetone)dipalladium(0) (99 mg, 0.10 mmol, 0.06 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 111 mg, 0.19 mmol, 0.12 equiv.). The mixture was degassed and purged with nitrogen (3 cycles) and then heated to 98-100° C. After 4 h, the mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. After drying over Na2SO4, the solvent was evaporated, and the residue was purified by CC (SiO2, CH2Cl2/EtOAc 8:1 to 3:1) to obtain the product (791 mg, 63%) as a light yellow oil. LC-MS (ESI) m/z 496 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[ClH:11]>O>[ClH:11].[CH:1]1([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC1CC1
Agent: Cl
Solvent: O
Product: O=C(O)CNC1CC1

Procedure:
Ethyl cyclopropylaminoacetate was stirred in a mixture of concentrated hydrochloric acid and water until the reaction had subsided. The mixture was then heated to reflux for 2 hours. The resulting solution was evaporated to give a white solid which was triturated with acetone and recrystallised from methanol/ethyl acetate to give cyclopropylaminoacetic acid hydrochloride of melting point 189°-191° C. (decomposition).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([Cl:29])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Clc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=4)[CH:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:14]3[CH3:29])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(=O)C=CC(=O)C=C1.C([O-])(=O)C.[Na+]>CN(C)C=O.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=4)[C:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:14]3[CH3:29])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)CC1c2cc(OC)ccc2N(c2ncnc3cc(Cl)ccc23)C1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(OC)cc12

Procedure:
A solution of methyl 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetate hydrochloride (2.15g.) in dry dimethylformamide (50ml.; dried with calcium hydride) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.2g.). The mixture was heated on a steam bath for 2 hours and then an additional portion of the benzoquinone derivative (0.6g.) was added. After further heating for 1 hour, the solution was poured into water (500ml.) containing anhydrous sodium acetate (10g.). The mixture was extracted with chloroform (3 × 100ml.) and the solid residue, at the solvent interface, discarded. The chloroform extracts were washed successively with water, saturated sodium bicarbonate solution, water and brine, and then dried (MgSO4). Evaporation of the solution gave an oil, which was purified by chromatography on silica gel (100g.) in an increasing gradient of ether in petroleum ether (b.p. 40°-60° C.) (polarity increased by incremental addition of 10% v/v ether) to give methyl 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate as a yellow solid, m.p. 112°-114° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].FC(F)(F)CO>[NH:8]1[CH2:9][CH2:10][C:11]2([C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][O:14]2)[CH2:12][CH2:13]1
Reactant: c1ccc(CN2CCC3(CC2)OCc2ncccc23)cc1
Agent: [Pd]
Solvent: OCC(F)(F)F
Product: c1cnc2c(c1)C1(CCNCC1)OC2
Reaction time: 16 h
Yield: 113 %

Procedure:
A 2-necked round bottom flask was charged with 0.56 g (2.0 mmol) 1′-benzyl-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine] and 20 ml 2,2,2-trifluoroethanol. The reaction mixture was purged with argon prior to adding 0.21 g (10 mol-%) palladium on activated charcoal. The flask was evacuated, refilled with hydrogen and stirred for 16 h. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated to dryness to give the title compound (0.43 g, quantitative, purity of approx. 90%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28](NCC(O)=O)=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C[N:46]([C:48]([O:52]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:10][N:9]2[CH2:28][C:48]([NH2:46])=[O:52])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(CC(N)=O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.37 h
Yield: 70.7 %

Procedure:
To a mixture rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid (25.4 mg, 0.048 mmol, example 17) in N,N-dimethyl formamide (2.5 mL) was added DIPEA (44.5 mg, 0.344 mmol) and HATU (30.3 mg, 0.080 mmol). After it was stirred at rt for 22 min, ground ammonium chloride (6.6 mg, 0.12 mmol,) was added. After 3 hrs the reaction mixture was extracted with EtOAc, and washed with water, 10% ammonium chloride, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetamide (16.3 mg, 64.3%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1>C(O)C.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[C:7](=[O:20])[C:6]3[CH:21]=[C:2]([F:1])[C:3]([NH:22][CH3:23])=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:16][CH:15]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc([N+](=O)[O-])cc1)CO2
Agent: [Pd]
Solvent: CCO
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)cc1)CO2
Yield: 101.3 %

Procedure:
To a suspension of 6-fluoro-7-(methylamino)-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.108 g, 0.33 mmol) in ethanol (6 mL) under Ar was added 10% Pd/C (0.04 g, 0.03 mmol Pd). The mixture was hydrogenated under 1 atm H2 overnight, filtered through Celite and concentrated to give 0.096 g (98%) of 3-(4-aminophenyl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 1.37 min; ES-MS (M+H)+=288.0; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3 H), 5.5 (s, 2 H), 6.2 (d, 1 H), 7.2 (d, 2 H), 7.3 (d, 2 H), 7.4 (d, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:10]([C:12]([CH3:19])([C:16](Cl)=[O:17])[C:13](Cl)=[O:14])[CH3:11].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[C:6]2[C:7]=1[C:16](=[O:17])[C:12]([CH2:10][CH3:11])([CH3:19])[C:13]2=[O:14]
Reactant: Cc1ccc(Cl)cc1C
Reactant: CCC(C)(C(=O)Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1(C)C(=O)c2c(Cl)cc(C)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a mixture of 28 ml of 4-chloro-o-xylene and 37.6 g of ethylmethylmalonyl chloride in 300 ml of dry dichloromethane was added slowly 26.7 g of AlCl3 under the current of nitrogen gas at -10° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 g of ice, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 24.67 g of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[IH:19]>C(Cl)Cl>[I:19][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1
Reactant: I
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2-chloro-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 11) (167.5 g, 614.34 mmol) in DCM (1325 mL) was added HI (57% in water) (405.23 mL, 3071.7 mmol) dropwise. The reaction was then stirred at room temperature overnight. Additional DCM (500 mL) was added, and the reaction was filtered. The solid was dried then transferred into a beaker containing water (1 L) and EtOAc (1.25 L). The aqueous was basified to pH 10 with K2CO3, and the layers were stirred until all the solid dissolved. Sodium metabisulfite (8.75 g) was added and the layers were stirred until all solid dissolved. The layers were separated, and the aqueous was re-extracted with EtOAc (200 mL). The combined organics were then dried over MgSO4, filtered and concentrated in vacuo to give the title material (D12) (205.68 g, 564.9 mmol, 92% yield) as a pale orange solid. NMR indicated this was >95% pure.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[N:17][N:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:19]=3)[CH:6]=[CH:5][C:4]1=2.Cl[CH2:28][CH2:29][CH2:30][CH2:31][O:32]C(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[N:17][N:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH2:22][CH2:21]4)[CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cn(C4CCNCC4)nn3)ccc21
Reactant: CC(=O)OCCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3cn(C4CCN(CCCCO)CC4)nn3)ccc21

Procedure:
The preparation was carried out as already described starting from 24 mg (0.06 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,3-triazol-1-yl]piperidine hydrochloride and 13 μl (0.11 mmol) of acetic acid 4-chlorobutyl ester. The protecting group was cleaved off by means of a 1N sodium hydroxide solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [C:1]1([S:11]([N:14]2[CH:18]([C:19](O)=[O:20])[CH2:17][CH:16]3[CH2:22][CH2:23][CH2:24][CH:15]23)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C(N1CCOCC1)C.C[Si]([NH:43][OH:44])(C)C>CN(C=O)C>[OH:44][NH:43][C:19]([CH:18]1[N:14]([S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])[CH:15]2[CH2:24][CH2:23][CH2:22][CH:16]2[CH2:17]1)=[O:20]
Reactant: O=C(O)C1CC2CCCC2N1S(=O)(=O)c1cccc2ccccc12
Reactant: C[Si](C)(C)NO
Agent: CCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Product: O=C(NO)C1CC2CCCC2N1S(=O)(=O)c1cccc2ccccc12
Temperature: 80 °C

Procedure:
200 mg (0.56 mmol) of 1-(naphthaline-1-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 10 ml of DMF, after which 0.61 mmol of ethyl chloroformate, 1.23 mmol of N-ethylmorpholine and 1.68 mmol of trimethylsilylhydroxylamine were added. After the mixture had been heated at 80° C. for 6 h, the solvent was removed under reduced pressure and the crude product was purified using chromatographic methods.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[N:21](COCC[Si](C)(C)C)[C:20](=[O:30])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:18]=3)[N:13]=2)[CH:11]=1)=[O:6])[CH3:3].O1CCOCC1>CCOCC>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[NH:21][C:20](=[O:30])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:31][C:32](=[O:39])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:18]=3)[N:13]=2)[CH:11]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NC(=O)c4ccccc4)cc3c(=O)n2COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3ccc(NC(=O)c4ccccc4)cc3c(=O)[nH]2)c1
Yield: 79.8 %

Procedure:
Hydrochloric acid (4M in dioxane, 2.0 mL, 8.0 mmol) was added to a solution of 1-[6-benzoylamino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.239 g, 0.488 mmol) and dioxane (2.0 mL). The reaction mixture was stirred at room temperature for 18 h, at which point ether (10 mL) was added and the precipitate was collected to yield the titled compound (0.157 g, 86% yield). MS (ESI/Cl): mass calcd. for C21H17N5O4, 403.1; m/z found, 404.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.87 (s, 1H), 10.62 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 8.32 (s, 1H), 8.23 (dd, J=8.9, 2.4 Hz, 1H), 8.06-7.96 (m, 2H), 7.84-7.49 (m, 4H), 4.31 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[N:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:13]=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CO>[CH3:8][C:2]([O:9][C:10]1[N:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:13]=[CH:12][CH:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccnn1-c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1ccnn1-c1cccc2ccccc12)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-yloxy)propanoate (80 mg, 0.25 mmol), aqueous sodium hydroxide solution (10%, 5 mL) and methanol (5 mL) was stirred at reflux for 2 hours. The reaction was then cooled to room temperature and the methanol removed. Water was added, neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded 2-Methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-yloxy)propanoic acid as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.4 (s, 1H), 8.09 (m, 2H), 7.65 (m, 6H), 5.78 (d, 1H), 1.37 (s, 6H).