Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([Cl:15])[CH:5]=1)(=O)[NH2:2].N1C=CC=CC=1>>[Cl:14][C:12]1[CH:13]=[C:4]([C:1]#[N:2])[CH:5]=[C:6]([Cl:15])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Cl)cc(C(N)=O)cc1Cl
Solvent: c1ccncc1
Product: COC(=O)c1c(Cl)cc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of methyl 4-carbamoyl-2,6-dichlorobenzoate (100 mg, 0.4 mmol) in pyridine (2 mL) trifluoro-acetic anhydride (0.11 ml, 0.8 mmol) was added drop wise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The contents were poured into ice cold water and the precipitated solid was filtered, washed with water and dried to yield methyl 2,6-dichloro-4-cyanobenzoate (55 mg, 88%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[CH:16][C:7]=4[O:6][C@H:4]([CH3:5])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[N:12]=[CH:11][N:10]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1
Reactant: COc1cccc(Cn2ncc3cc(N)ccc32)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Product: COc1cccc(Cn2ncc3cc(Nc4ncnc5cccc(O[C@H](C)C(=O)N(C)C)c45)ccc32)c1
Yield: 58 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (220 mg, 0.84 mmol) and 1-(3-methoxybenzyl)-1H-indazol-5-amine (1.1 equivalents) were reacted to give the title compound as a beige foam (242 mg, 58%); NMR spectrum (CDCl3) 1.72 (d, 3H), 3.05 (s, 3H), 3.14 (s, 3H), 3.73 (s, 3H), 5.42 (q, 1H), 5.57 (s, 2H), 6.74 (s, 1H), 6.78-6.81 (m, 3H), 7.20 (t, 1H), 7.36 (d, 1H), 7.46 (d, 1H), 7.59 (t, 1H), 7.80 (d, 1H), 8.06 (s, 1H), 8.40 (s, 1H), 8.61 (s, 1H), 10.85 (br s, 1H); Mass spectrum MH+ 497.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[NH:6][C:5]2=O.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[Cl:22]
Reactant: O=c1[nH]c(-c2ccccc2F)nc2ccc(Br)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Temperature: 0 °C
Yield: 90 %

Procedure:
6-Bromo-2-(2-fluoro-phenyl)-3H-quinazolin-4-one from Step C (1.5 g, 4.6 mmol) was suspended in chloroform in a 50 ml round bottomed flask equipped with magnetic stirrer. The flask was cooled to 0° C. and to it was added thionyl chloride (1.6 ml) drop wise followed by N,N-dimethyl formamide (0.01 ml) and the mixture heated to 80° C. for 4 hrs. The solvent was removed by evaporation in a rotary evaporator to leave a title compound as a solid (1.43 g, 90%). MS (ES) 338 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][NH:21][N:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[C:19]3[N:18]=2)=[CH:5][CH:4]=1
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Product: COc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1
Yield: 59.4 %

Procedure:
Reaction of 1-(4-methoxy-phenyl)-4,4,4-trifluoro-butane-1,3-dione (123 mg, 0.5 mmol), prepared from commercially available 4-methoxy-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (110 mg, 59%). MS (ISP) 371.2 [(M+H)+]; mp 244° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][CH:8]=[N:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:10]1[N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[N:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cn1nccc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccnn1CC(=O)NN
Temperature: 25 °C
Yield: 95 %

Procedure:
As described for example 112a, (5-methyl-pyrazol-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 8 h. The mixture was cooled to rt and the precipitated product was filtered off, dried and crystallized from toluene. The title compound (95% purity, based on NMR) was obtained as a white solid (yield: 45%). 1H-NMR (300 MHz, DMSO): δ=2.24 (s, 3H), 4.29 (s, 2H), 4.65 (s, 2H), 6.00 (d, J=1 Hz, 1H), 7.55 (d, J=1 Hz, 1H), 9.27 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.CN(C)/[CH:12]=[C:13](/[C:19](=[O:28])[C:20]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:21]=1F)\[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>>[I:26][C:24]1[CH:25]=[C:20]2[C:21](=[CH:22][CH:23]=1)[N:9]([CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]2=[O:28]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cn(CCN2CCOCC2)c2ccc(I)cc2c1=O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
2-Morpholinoethanamine (0.88 g, 6.7 mmol) was added to the stock solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.38M, 18 mL, 7 mmol) and the mixture was heated at 40° C. for 3 h. The solvent was removed in vacuo and the resulting residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (5 mL) and potassium carbonate powder (1.2 g, 10 mmol) was added. The reaction was heated at 70° C. for a further 3 h then cooled to room temperature. The crude reaction mixture was placed into a fridge for a 3 h. The solid precipitate that formed was collected by filtration, washed with a small amount of dimethylformamide, followed by water, then dried under high vacuum.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(OC)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and (6-methoxypyridin-3-yl)boronic acid (from Aldrich). LCMS calculated for C22H23N4O3(M+H)+: m/z=391.2. Found: m/z=391.1.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH:13]2[C@:11]([OH:15])([CH2:12]2)[C@@H:10]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1>[Pd].CO>[C:16]1([C@@H:10]2[NH:9][CH2:14][CH:13]3[C@:11]2([OH:15])[CH2:12]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O[C@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O[C@]12CC1CN[C@H]2c1ccccc1

Procedure:
The HCl salt of the starting material Intermediate 28, mixture of diastereomers (1R,2S)-3-Benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexan-1-ol (1.2 g, 4.1 mmol), was combined with palladium on carbon 20% (Pearlman's catalyst, 0.7 g) and MeOH (35 mL) and hydrogenated at 40 psi for 16 hours. The material was filtered thru celite and concentrated to yield the title compounds as a mixture of diastereomers (0.88 g, quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]2[N:21]=[C:22](S(C)(=O)=O)[N:23]=[C:4]2[N:3]=1.[O-:28][CH2:29][CH3:30].[Na+]>C(O)C>[CH2:29]([O:28][C:22]1[N:23]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([S:15]([F:19])([F:18])([F:16])([F:17])[F:20])=[CH:11][CH:10]=3)[N:5]2[N:21]=1)[CH3:30]
Reactant: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)n2nc(S(C)(=O)=O)nc2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(C)cc(Nc3ccc(S(F)(F)(F)(F)F)cc3)n2n1
Temperature: 120 °C

Procedure:
Intermediate 10 (0.15 g, 0.349 mmol) was added to sodium ethoxide (ALDRICH, 0.071 g, 1.048 mmol) in ethanol (3 mL). The mixture was heated under microwave irradiation at 120° C. for 30 minutes. Solvent was removed under vacuum and the crude mixture was purified by flash chromatography (Si, eluting with DCM: MeOH mixtures from 100:0 to 90:10%). The title compound was obtained as a white solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[O:20][CH2:21][C:22]([CH3:25])(O)[CH3:23]>CS(O)(=O)=O.CCCCCC>[CH3:15][O:16][C:17]1[CH:28]=[CH:27][C:26]2[C:22]([CH3:25])([CH3:23])[CH2:21][O:20][C:19]=2[CH:18]=1
Reactant: COc1cccc(OCC(C)(C)O)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCCC
Product: COc1ccc2c(c1)OCC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
To a solution of 50 g (0.352 mol) of phosphorous pentoxide in 500 ml of methanesulfonic acid was added dropwise 20 g (0.101 mol) of 1-(3-methoxyphenoxy)-2-methyl-2-propanol over a 30 min period. The reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was poured into 1.5 l of ice water and extracted with ether. The combined extracts were dried and evaporated. The residue was filtered through silica gel (500 g) using a gradient from hexane to 10:90 (v/v) of ether:hexane as eluent, There was obtained 13.2 g (74.06 mmol, 72%) of 2,3-dihydro-6-methoxy-3,3-dimethylbenzofuran. This material was dissolved in 75 ml of toluene an 8.12 g (0.11 mol) of dimethylformamide was added. The mixture was cooled in an ice water bath and 14.23 g (92.8 mmol) of phosphorous oxytrichloride was added dropwise. The reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to ambient temperature and poured into 300 ml of 2N sodium hydroxide solution. The organic phase was washed with 1N hydrochloric acid, water, saturated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel (150 g) using a gradient of from hexane to 25:75 (v/v) ether:hexane as eluent. There was obtained 10.3 g (49.9 mmol, 68%) of 2,3-dihydro-6-methoxy-3,3-dimethyl-5-benzofurancarboxaldehyde as white crystals; mp 75°-76° C.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]1=2)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[N:20]1[C:28]([NH2:29])=[C:27]2[C:23]([N:24]=[CH:25][NH:26]2)=[N:22][CH:21]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]2=3)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:29]1[C:28]1[N:20]=[CH:21][N:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[N:24]2
Reactant: O=CC(CO)OC(C=O)n1cnc2c(=O)[nH]cnc21
Reactant: Nc1ncnc2nc[nH]c12
Solvent: CO
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2ncnc3nc[nH]c23)C1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (inosinedialdehyde), (2.66 g) was dissolved in a mixture of methanol (100 ml) and water (100 ml). To the solution was added adenine (1.35 g). The mixture was stirred at ambient temperature for one day and filtered. The filtrate was evaporated in vacuo at 35° C. The residue was triturated with acetone to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(6-purinyl)morpholin-2-yl]hypoxanthine (3.20 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][CH2:16][CH2:17][OH:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][CH2:16][CH2:17][OH:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(NCCO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 1 mmol) in dichloromethane (5 mL) was added 2-Amino ethanol (0.073 mg, 1.2 mmol) and NaBH(OAc)3 (0.3 g, 1.4 mmol). The resulting mixture was stirred at room temperature overnight and partitioned between dichloromethane and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was directly used into the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](Br)=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:30]=[O:31].O>O1CCCC1>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([CH:30]=[O:31])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1cc2nc(-c3ccc(Br)c4ccccc34)[nH]c2cc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)c2ccccc12
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
To a solution of 5,6-dichloro-2-(4-bromo-1-naphthyl)benzimidazole (160 mg, 0.408 mmol) in tetrahydrofuran (6 mL) were added n-butyllithium (1.6 mol/L; 0.64 mL) and dimethylformamide (0.077 mL, 1.0 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (2:1 hexane/ethyl acetate) to afford 5,6-dichloro-2-(4-formyl-1-naphthyl)benzimidazole (72 mg, 52%).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[C:19]([C:21]1([OH:27])[CH2:25][CH2:24][CH2:23][CH:22]1[F:26])#[CH:20]>>[F:26][CH:22]1[CH2:23][CH2:24][CH2:25][C:21]1([C:19]#[C:20][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1)[OH:27]
Reactant: C#CC1(O)CCCC1F
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Product: NC(=O)c1cc2n(n1)-c1cc(C#CC3(O)CCCC3F)ccc1OCC2

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with a 1-ethynyl-2-fluorocyclopentanol to give a mixture of titled compounds after purification by HPLC.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:41][C:18]3=[N:19][CH:20]=[C:21]([C:39]#[N:40])[C:22]([NH:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)=[C:17]3[C:16]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[C:39]([C:21]1[C:22]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[C:17]2[C:16]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[O:41][C:18]2=[N:19][CH:20]=1)#[N:40]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2c(C#N)cnc3oc(-c4ccc(OCc5ccccc5)cc4)c(-c4ccccc4)c23)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCNc2c(C#N)cnc3oc(-c4ccc(O)cc4)c(-c4ccccc4)c23)CC1

Procedure:
A mixture of 8c (200 mg, 0.303 mmol, 1.0 equiv) and 10% Pd on carbon (30 mg) in EtOAc at 25° C. was exposed to a hydrogen atmosphere (balloon). Upon consumption of the starting material as indicated by TCL, the mixture was filtered and solvent removed in vacuo. The resulting phenol 8b was advanced without further purification. MS (MH+) 540; Calculated 539.3 for C31H33N5O4.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]1([O:16][CH3:17])[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:10][CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:11][O:10][C:9]1[CH:12]=[C:13]([CH:14]=[CH:15][C:8]=1[O:16][CH3:17])[C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5]
Reactant: COc1ccccc1OC
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC
Reaction time: 6 h
Yield: 64 %

Procedure:
70 g (0.7 mol) of succinic anhydride and 96.6 g (0.7 mol) of veratrole were dissolved in 2,000 ml of methylene chloride, and 237 g (1.75 mol) of anhydrous aluminum chloride was added thereto at room temperature. The mixture was stirred at the same temperature for 6 hours. The reaction solution was left to stand for 15 hours. Then, 1,600 ml of 6N hydrochloric acid was dropwise added to the reaction solution under stirring and the mixture was further stirred for one hour. The organic layer was separated, and 300 ml of water was added thereto. The mixture was adjusted to pH7.5 with a saturated sodium bicarbonate aqueous solution. The aqueous layer was separated and adjusted to pH2.5 with 6N hydrochloric acid. The aqueous layer was left to stand in a refrigerator for two days. Then, the precipitated crystals were collected by filtration, washed with water and dried to obtain 106.8 g (yield: 64%) of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].I[CH2:34][C:35]([NH2:37])=[O:36]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[N:29][CH2:34][C:35](=[O:36])[NH2:37])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: NC(=O)CI
Reactant: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=NCC(N)=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl sulfoximide (500 mg, 0.00108 mol) in DMF(2.5 mL) was added Sodium hydride (170 mg, 0.0036mol) at 25-30° C. under nitrogen atmosphere. Reaction mixture was stirred at 40-45° C. for 3 hr. Reaction mixture was cooled to 0-5° C. and to this was added iodoacetamide (240 mg, 0.0013 mol) and stirred for 12 hr at 25-30° C. Subsequent work up and column purification (100-200 mesh silica gel, 2% methanol in chloroform) gave 90 mg of titled product in 16% yield.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][C:11]3([O:18][C:17](=[O:19])[NH:16][C:15]4[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=4)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl.[CH2:25]([O:27][NH2:28])[CH3:26]>N1C=CC=CC=1.CO>[CH2:25]([O:27][N:28]=[C:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH2:13][CH2:12][C:11]3([O:18][C:17](=[O:19])[NH:16][C:15]4[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=4)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1)[CH3:26]
Reactant: O=C1CCC(N2CCC3(CC2)OC(=O)Nc2ccccc23)CC1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCON=C1CCC(N2CCC3(CC2)OC(=O)Nc2ccccc23)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1′-(4-oxocyclohexyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (Compound No. 64) (31 mg, 0.10 mmol) was dissolved in anhydrous pyridine (500 μL), treated with of O-ethylhydroxylamine hydrochloride (7 mg, 0.12 mmol) and stirred at 60° C. for 30 minutes. The reaction was cooled to room temperature, diluted with methanol (500 μL) and subjected to reverse-phase HPLC purification (2-30% CH3CN gradient [w/0.1% TFA (aq)] over 10 minutes, 1.0 mL injected, 35 mL/min) to provide 1′-(4-(ethoxyimino)cyclohexyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 3). LC/MS m/z 358.0 [M+H]+, retention time 1.64 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([F:24])([F:23])[F:22])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([O:27][CH3:28])[C:3]=1[C:4]#[N:5].O.[NH2:30][NH2:31]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:30][NH:31]3)=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([F:22])([F:24])[F:23])[N:13]=1
Reactant: NN
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Yield: 54.9 %

Procedure:
2-Fluoro-4-{2-(methylamino)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile (131 mg, 0.331 mmol) was dissolved in ethanol (3 mL) in a 5 mL sealable vial. Hydrazine monohydrate (0.487 mL, 9.94 mmol) was added, the vial was capped, and the reaction was heated at 100° C. overnight. The reaction was concentrated, dissolved in 2 mL of DMSO and purified in HPLC (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 mL/min, 18% CH3CN/H2O, 0.1% TFA to 43% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the water left behind was added saturated NaHCO3, then extracted with EtOAc (3×15 mL). The organic was washed with brine, dried over MgSO4, filtered, concentrated, and transferred to a haystack vial. Water (1 mL) was added, and the resulting mixture was freeze dried to afford the title compound (74 mg) as a light yellow solid. LC-MS (ES) m/z=408 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.95-2.03 (m, 2H), 2.05 (bs, 2H), 2.77 (d, J=3.3 Hz, 3H) 3.47 (d, J=8.8 Hz, 1H) 3.62 (d, J=4.6 Hz, 1H), 3.87 (s, 3H), 4.98 (bs, 2H), 5.08 (bs, 1H), 6.39 (bs, 1H), 6.64 (bs, 1H), 6.88 (bs, 1H), 7.43 (bs, 1H), 11.50 (bs, 1H).