Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([O:25][C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1nc(Br)ccc1[N+](=O)[O-]
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(OC2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 4 h
Yield: 17.9 %

Procedure:
A mixture of 6-bromo-2-methoxy-3-nitropyridine (1.5 g, 6.44 mmol), 1-benzyl-pyrrolidin-3-ol (1.14 g, 6.44 mmol) and K2CO3 (0.89 g, 6.44 mmol) in dimethylformamide (DMF) (20 ml) was stirred at room temperature for 24 h and at 40° C. for 4 h. After evaporation of the solvent under reduced pressure the residue was purified by silica gel chromatography with dichloromethane/methanol (10:0; 9:1; 7:3; 0:10) as eluent to provide 380 mg (18.1%) of the product.
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]([C:24]4[C:25]([F:38])=[C:26]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])[CH:27]=[CH:28][C:29]=4[F:30])=[O:23])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)C>CO.[Pt](=O)=O>[F:38][C:25]1[C:24]([C:22]([C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:10]4[CH:11]=[N:12][C:7]([CH2:6][CH2:5][CH3:4])=[CH:8][CH:9]=4)[CH:14]=3)[NH:19][CH:20]=2)=[O:23])=[C:29]([F:30])[CH:28]=[CH:27][C:26]=1[NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(C#CCN(CC)CC)nc4)cc23)c1F
Agent: O=[Pt]=O
Solvent: CO
Product: CCCc1ccc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(NS(=O)(=O)CCC)c4F)c3c2)cn1
Reaction time: 1 h

Procedure:
Propane-1-sulfonic acid (3-{5-[6-(3-diethylamino-prop-1-ynyl)-pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-2222, 20.3 mg, 0.0359 mmol) was dissolved in 0.14 mL of methanol. Platinum dioxide (0.81 mg, 0.0036 mmol) was added and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was filtered through a bed of celite and the filtrate was concentrated. The crude material was purified by flash silica gel chromatography, eluting with a gradient of 15% methanol in dichloromethane to 1% methanol in dichloromethane. The appropriate fractions were combined and concentrated to provide the desired compound as a solid. MS (ESI) [M+H+]+=499.4.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.S(Cl)(Cl)=O.[OH-].[Na+].[NH:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1>COCCOC.O.CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:24]3[CH2:27][CH:26]([OH:28])[CH2:25]3)=[O:17])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC1CNC1
Reactant: O=C(O)CCOCCc1ccc2sccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
In 15 mL of 1,2-dimethoxyethane was dissolved 10.0 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid. Thereto were added 0.1 mL of N,N-dimethylformamide and 5.23 g of thionyl chloride, which was then stirred at room temperature for 1.5 hours. This reaction solution was dropwise added to a mixed solution of 50 mL of water, 7.19 g of sodium hydroxide and 7.69 g of 3-azetidinol 1/2 tartrate at 5 to 15° C., which was then stirred at same temperature for 2 hours. Thereto was added 90 mL of water. The precipitate was collected by filtration to provide 11.0 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol as white solid form.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:15]#[N:16])([CH3:11])[CH3:10].C(N(C)C(C)C)(C)C>C(Cl)Cl>[CH3:24][C:21]([C:18]1[CH:17]=[C:14]([CH:13]=[C:12]([C:9]([CH3:11])([CH3:10])[CH3:8])[C:19]=1[O:20][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]#[N:16])([CH3:22])[CH3:23]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1cc(C#N)cc(C(C)(C)C)c1O
Agent: CC(C)N(C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
2-Methoxyethoxymethyl chloride (4.1 g, 0.032 mole) is added dropwise to a 0° C. mixture of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzonitrile (Louis A. Cohen, Journal of Organic Chemistry 22, 1333, 1957) (5.0 g, 0.022 mole) and diisopropylaminomethane (4.2 g, 0.032 mole) in methylene chloride (50 ml). The mixture is allowed to warm to room temperature and stir 18 hours. The solution is diluted with methylene chloride (25 ml) and washed with water (25 ml), cold 2M HCl (20 ml), saturated aqueous NaCl, and dried over MgSO4. Filtered and concentrated in vacuo to obtain 6.7 g (6.9 g theor., 97%) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile as a yellow oil.
Reaction SMILES: C[N-]C.C[N-]C.[CH3:7][C:8]1[CH:9]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[CH2:18][O:19][Ti+2:20])[C:10]([CH3:15])=[C:11]([CH3:14])[C:12]=1[CH3:13].C[Si](C)(C)[Cl:27]>CCCCC>[Cl-:27].[Cl-:27].[CH3:15][C:10]1[CH:9]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[CH2:18][O:19][Ti+2:20])[C:8]([CH3:7])=[C:12]([CH3:13])[C:11]=1[CH3:14]
Reactant: C[Si](C)(C)Cl
Agent: CC1=C(C)C(c2ccccc2CO[Ti+2])C(C)=C1C
Agent: C[N-]C
Solvent: CCCCC
Product: [Cl-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzyloxytitanium bis(dimethylamide) (0.84 g, 3.1 mmol) in pentane (15.2 mL) was added dropwise a solution of trimethylchlorosilane (3.67 g, 33.8 mmol) in pentane (5.0 mL) at 0° C. The mixture was stirred at room temperature for 15 hrs. 2-(2,3,4,5-Tetramethylcyclopentadienyl)benzyloxytitanium dichloride (1.00 g, yield 94.3%) was obtained as an yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[O:12]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CO>[O:12]([C:19]1[CH:20]=[C:21]([CH:22]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:24]=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: O=C1C(=Cc2cccc(Oc3ccccc3)c2)Oc2cc(O)ccc21
Temperature: 25 °C

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-phenoxybenzaldehyde 1.27 ml were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.10 g.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([N:11]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)C(=O)C)=[C:9]([CH:23]([CH3:25])[CH3:24])[C:8](=[O:26])[NH:7][C:6]1=[O:27])[CH:2]=[CH:3][CH3:4].C[O-].[Na+].[NH4+].[Cl-]>CO>[CH2:1]([N:5]1[C:10]([NH:11][C:15]2[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=2)=[C:9]([CH:23]([CH3:24])[CH3:25])[C:8](=[O:26])[NH:7][C:6]1=[O:27])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(N(C(C)=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC=CCn1c(Nc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a stirred solution of N-(3-but-2-enyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N-(3,5-dimethyl-phenyl)-acetamide (107) (100 mg, 0.27 mmol) in methanol (3 mL), was added sodium methoxide (73 mg, 1.35 mmol). After 4 hr., the mixture was neutralized with excess NH4Cl and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 62 mg (70%) of a white solid. m.p. 186-187° C.; 1H-NMR (200 MHz, CDCl3) δ 1.17 (6H, d, J=6.9 Hz), 1.64-1.67 (3H, m), 2.24 (6H, s), 2.86 (1H, m), 4.25-4.30 (2H, m), 5.33 (1H, s), 5.48-5.54 (2H, m), 6.32 (2H, s), 6.60 (1H, s), 8.42 (1H, s); m/z (EI) 327 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>C1(P([Pd-4](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)C=CC=CC=1>[CH3:15][O:14][C:12]([C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:13]
Reactant: COC(=O)c1ccc(Br)cc1C(=O)OC
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1C(=O)OC

Procedure:
n.m.r. δ values include 3.93 (s, 3 H), 3.94 (s, 3 H), 7.65 (t, 1 H), 7.78 (dd, 1 H), 7.86 (d, 1 H), 7.92-7.95 (m, 2 H), 8.26 (dd, 1 H), 8.46 (t, 1 H); from dimethyl 4-bromophthalate (1.80 g), tetrakis(triphenylphosphino)palladium(0) (246 mg) and 3-nitrophenylboronic acid (1.3 g)
Reaction SMILES: Cl.[F:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][NH:5][CH2:4]1.C([O-])(O)=O.[Na+].[C:15](Cl)(=[O:28])[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C1COCC1.O>[F:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:15]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:28])[CH2:4]1
Reactant: O=C1CCNCC1F
Reactant: O=C(Cl)OCc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)OCc2ccc3ccccc3c2)CC1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a suspension of 3-fluoropiperidin-4-one hydrochloride (35.66 g, 232.2 mmol) in THF (800 mL) at 0° C. was added a solution of NaHCO3 (46.81 g, 557.3 mmol) in water (800 mL). After most of the bubbling had subsided the ensuing solution was treated with a solution of naphthalen-2-ylmethyl carbonochloridate (56.36 g, 255.4 mmol) in THF (300 mL) dropwise, over 30 minutes. The mixture was allowed to warm to ambient temperature over 16 hours with vigorous stirring. The mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, then dried over Na2SO4, filtered arid concentrated. The residue was triturated with methanol and the resulting solid was filtered and dried in vacuo to afford 41.8 g (60%) of desired product as a cream-colored powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.O.[NH2:12][NH2:13].O.C(OCC)(=O)C>C(O)CCC>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:13][N:12]=[CH:7]2
Reactant: O=Cc1cc(Br)ccc1F
Reactant: NN
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc2[nH]ncc2c1
Temperature: 65 °C
Yield: 29.5 %

Procedure:
To an orange solution of 5-bromo-2-fluorobenzaldehyde (3.0 g, 14.78 mmol) in n-butanol (6 mL) was added hydrazine hydrate (11.1 g, 10.78 mL, 221.66 mmol) and the thick orange slurry was heated to 125° C. (became clear at 65° C.) in an oil bath for 21 h and cooled to rt. The mixture was poured into water (100 mL) and ethyl acetate (300 mL). The aqueous layer was isolated and extracted with ethyl acetate (100 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated. The product was isolated by column chromatography (33% ethyl acetate in hexanes) as a cream colored solid (0.86 g, 30%). LC-MS [M+H]+=197.1, RT=2.64 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](O)=O.C[NH2:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:14]
Reactant: COc1ccccc1CC(=O)O
Reactant: CN
Product: COc1ccccc1CCN

Procedure:
Synthesized according to typical procedures C and D from 2-methoxyphenylacetic acid and methylamine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:13]=[CH:12]3)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:36]=[C:37]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:38]=[CH:39][CH:40]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:38]=[CH:39][CH:40]=4)[N:3]=3)=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: C=CC(=O)Nc1cccc(N)c1
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccn3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of (4-chloro-[1,3,5]triazin-2-yl)-(1-pyridin-2-ylmethyl-1H-indazol-5-yl)-amine (Step 3) (90.0 mg, 0.266 mmol) in IpOH (3.0 ml) was added DIEA (0.07 mL, 0.40 mmol) and N-(3-aminophenyl)acrylamide (47.5 mg, 0.293 mmol). The mix was heated at 100° C. for 18 h. The solution was cooled to RT. A precipitate fell out of solution, was filtered off and dried under reduced pressure to give N-{3-[4-(1-pyridin-2-ylmethyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide: MS m/z=464[M+H]+. Calc'd for C25H21N9O: 463.19.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:52][S:53][CH3:54])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].C(O)(=O)C.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:52][S:53][CH3:54])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CSC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C(C)(C)O)nc(CSC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
A mixture of 300 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-methylthiomethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (d) above] and 5 ml of a 25% v/v aqueous solution of acetic acid was stirred at 60° C. for 1 hour. At the end of this time, the resulting solution was mixed with 5 ml of water and cooled with ice. The trityl alcohol which appeared as crystals was filtered off, and the filtrate was concentrated by evaporation under reduced pressure. Acetic acid and water in the residue were removed by distillation as azeotropic mixtures with toluene, to give 217 mg of the title compound as an amorphous powder.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([Cl:31])[C:15]=2[N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)[NH:10][CH:9]=1.C(N(CC)CC)C.[Li+].[OH-]>ClCCl.CN1C(=O)CCC1.C1COCC1.CC#N.O>[C:1]([NH:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([Cl:31])[C:15]=2[N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:18]2)[NH:10][CH:9]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Reactant: CCCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Butyryl chloride (350 mg, 3.28 mmol) in anhydrous dichloromethane (0.5 mL) was added dropwise to a solution of (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (200 mg, 0.547 mmol; Example 91, Step A) and triethylamine (387 mg, 0.533 mL, 3.83 mmol) in NMP (1.0 mL) cooled on an ice-bath. The resulting mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with THF (10 mL), treated with an aqueous 2N LiOH solution (3 mL) and stirred for 1 hour. The THF was evaporated, and the residue was stirred with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-80% CH3CN/water, 25CV) to yield (R)-tert-butyl 1-(3-butyramido-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (221 mg, 93% yield) as a solid. LCMS (APCI+) m/z 336.1, 436.1 (M+H)+, Retention time=3.75 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:71]=[CH:70][C:53]2[NH:54][C:55]([CH:57]([NH2:69])[CH2:58][C:59]3[CH:64]=[CH:63][C:62]([O:65][CH:66]([F:68])[F:67])=[CH:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:71]=[CH:70][C:53]2[NH:54][C:55]([CH:57]([NH:69][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:60]=[CH:61][C:62]([O:65][CH:66]([F:68])[F:67])=[CH:63][CH:64]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: NC(Cc1ccc(OC(F)F)cc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(Cc2ccc(OC(F)F)cc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chloro-1H-benzimidazol-2-yl)-2-(4-difluoromethoxyphenyl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.36 (silica gel: dichloromethane/ethanol=9:1); C29H27ClF2N4O3 (553.01); mass spectrum: (M+H)+=553/555 (chlorine isotope).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:26][CH:25]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1C(=O)OC
Reaction time: 96 h

Procedure:
1 eq. of dimethyl 4-hydroxyphthalate, 1.1 eq. of potassium carbonate and 1.1 eq. of 4-methoxybenzyl chloride were stirred in DMF at RT. After 4 days, the mixture was worked up according to a standard procedure. Dimethyl 4-(4-methoxybenzyloxy)phthalate was isolated as a colorless oil. MS: 331 ((M+1)+)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([S:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:29])[CH:21]=1)(=[O:19])=[O:18])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])=[CH:21][C:22]=2[CH3:29])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(C)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(C)c1

Procedure:
4 g of 4-bromo-2-methylbenzonitrile was used in Procedure Q with ethanethiol to afford 4-(ethylthio)-2-methylbenzonitrile. 2 g of 4-(ethylthio)-2-methylbenzonitrile was reacted via Procedure R to give 4-(ethylsulfonyl)-2-methylbenzonitrile. 2.5 g of 4-(ethylsulfonyl)-2-methylbenzonitrile was reacted via Procedure T to give 4-(ethylsulfonyl)-2-methylbenzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(ethylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)-2-methylbenzamide. MS (Q1) 415.0 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:25]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)[CH2:26][CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][C:34]([C@H:31]4[CH2:32][CH2:33][C@H:28]([CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30]4)=[O:35])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(O)cc3)cc2)CC1
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(OC(=O)[C@H]4CC[C@H](CCC)CC4)cc3)cc2)CC1
Reaction time: 72 h

Procedure:
0.40 g of 4-hydroxy-4'-(trans-4-pentylcyclohexyl)biphenyl, 0.21 g of trans-4-propylcyclohexanecarboxylic acid and 0.025 g of (4-dimethylamino)pyridine were dissolved in 25 ml of dichloromethane and then 0.31 g of N,N'-dicyclohexylcarbodiimide was added portionwise within 10 minutes while stirring. The mixture was left to stand at room temperature for 3 days and then the precipitate was filtered off. The filtrate was diluted with dichloromethane, washed twice with 20 ml of saturated sodium bicarbonate solution each time and then with water, dried over sodium sulphate and concentrated. The crude trans-4-propylcyclohexanecarboxylic acid 4'-(trans-4-pentylcyclohexyl)-4-biphenylyl ester obtained was chromatographed on silica gel with hexane/dioxane (volume ratio 19:1). The fractions which were pure according to thin-layer chromatography were pooled and recrystallized from ethyl acetate. Yield 0.33 g; m.p. (C-S) 92° C., cl.p. (N-I) 319° C.; further phase transitions: S-S 154° C., S-S 218.5° C., S-N 240° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([NH:10][C:11]2[CH:24]=[C:23]3[C:14]([O:15][C:16]4[C:17]([F:33])=[CH:18][C:19]([O:31][CH3:32])=[CH:20][C:21]=4[C@:22]3([NH:28][C:29]#[N:30])[CH2:25][CH2:26][OH:27])=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]>CO.Cl>[CH2:1]([O:3][C:4]1[C:5]([NH:10][C:11]2[CH:24]=[C:23]3[C:14]([O:15][C:16]4[C:17]([F:33])=[CH:18][C:19]([O:31][CH3:32])=[CH:20][C:21]=4[C@@:22]43[CH2:25][CH2:26][O:27][C:29]([NH2:30])=[N:28]4)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccnc1Nc1ccc2c(c1)[C@](CCO)(NC#N)c1cc(OC)cc(F)c1O2
Agent: Cl
Solvent: CO
Product: CCOc1cccnc1Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(OC)cc(F)c1O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
(S)—N-(7-((3-ethoxypyridin-2-yl)amino)-4-fluoro-9-(2-hydroxyethyl)-2-methoxy-9H-xanthen-9-yl)cyanamide (160 mg, 0.355 mmol) was dissolved in methanol (10 ml) and three drops of concentrated HCl was added. The solution was stirred at room temperature for 30 minutes. The solution was quenched with water and saturated sodium bicarbonate, then extracted with ethyl acetate. The organics were then separated and concentrated. The product was purified via silica gel column chromatography (RediSep 40 g column) using 50-100% ethyl acetate in heptane to afford (S)—N7′-(3-ethoxypyridin-2-yl)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (40 mg, 0.089 mmol, 25.00% yield). MS m/z=451.0 [M+H].