Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C>[CH3:33][N:24]1[C:23](=[O:27])[CH:22]=[N:21][N:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=3)[CH2:15][CH2:14]2)[C:25]1=[O:26]
Reactant: CI
Reactant: O=c1cnn(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c(=O)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cnn(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c1=O

Procedure:
The compound 1 (3.77 g; 0.009 mol is added dropwise to a 60% suspension of sodium hydride in paraffin oil (0.77 g; 0.019 mol) in DMF (50 ml), followed, after stirring for 2 hours at room temperature, by iodomethane (1.4 g; 0.01 mol). After leaving overnight at room temperature, the mixture is concentrated to dryness under vacuum and then the residue is taken up in water (100 ml) and extracted with ethyl ether (2×50 ml). The dried organic phases (Na2SO4) are concentrated to dryness under vacuum to give an oil which crystallizes slowly.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:14][O:15][C:16]1[C:21]([CH:22]=[O:23])=[CH:20][CH:19]=[C:18]([O:24][CH3:25])[N:17]=1.[Cl-].[NH4+]>C1COCC1>[CH3:14][O:15][C:16]1[C:21]([CH:22]([OH:23])[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:19]=[C:18]([O:24][CH3:25])[N:17]=1
Reactant: COc1ccc(C=O)c(OC)n1
Reactant: C#Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of phenylacetylene (0.61 g, 5.98 mmol) in dry THF (10 mL), cooled to −78° C., was added 2.5 M nBuLi in hexanes (2.4 mL, 6.0 mmol). The mixture was stirred for 15 min at −78° C., followed by addition of a solution of 2,6-dimethoxypyridine-3-carbaldehyde (1.0 g, 6.0 mmol) in THF (10 mL) was added over 5 minutes. The reaction mixture was allowed to warm to 0° C. and saturated ammonium chloride was added. The resultant biphasic mixture was separated and extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10 to 30% ethyl acetate in cyclohexane) to afford the title compound (1.60 g, 99%) as a colourless gum. LCMS (Method B): RT=4.38 min, [M+H]+=270.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1cccc(Cl)c1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(Cl)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 174.1-176.1° C. 1H NMR (acetone-d6 /300 MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.48 (m, 1H), 7.29 (d, 1H, J=7.5 Hz), 7.17 (d, 1H, J=2.0 Hz), 7.08 (d, 1H, J=8.3 Hz), 6.73 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=6.5 Hz). FABLRMS m/z 403 (M-H). ESHRMS m/z 402.9752 (M-H, Calc'd 402.9729). Anal. Calc'd for C17H9Cl2F3O4 : C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.18; H, 2.00; Cl, 17.26.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[N:24]=[C:23]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[CH3:39])[N:22]=3)[C@H:17]([CH3:40])[CH2:16]2)=[C:12]([CH3:14])[CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[N:24]=[C:23]([N:34]3[CH2:38][CH2:37][CH2:36][C@H:35]3[CH3:39])[N:22]=[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:11]4[N:10]=[CH:9][C:8]([CH2:7][C:6]([OH:41])=[O:5])=[CH:13][C:12]=4[CH3:14])[CH2:16][C@H:17]3[CH3:40])[CH:26]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1

Procedure:
Stir a solution of (6-{4-[6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-pyridin-3-yl)-acetic acid tert-butyl ester (210 mg, 0.375 mmol) and 1 mL of TFA in DCM (10 mL) at room temperature for 16 h. Concentrate and partition between EtOAc and sat. NaHCO3. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify using flash chromatography eluting with MeOH-DCM (1:19) to give the title compound.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)[S:25][C:18]=12.[O:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47]O)[CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:13][C:14]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[O:32][CH2:47][CH2:46][N:43]3[CH2:44][CH2:45][O:40][CH2:41][CH2:42]3)[S:25][C:18]=12
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(O)c4)sc23)c(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Yield: 66.5 %

Procedure:
Diethylazodicarboxylate (0.6 mL, 3.84 mmol) was added to the solution of 160 (1.05 g, 2.75 mmol), 2-morpholinoethanol (0.5 mL, 3.84 mmol) and triphenylphosphine (1.01 g, 3.84 mmol) in tetrahydrofuran (27 mL). The reaction mixture was stirred until its completion, quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluent MeOH-DCM (2:98) to afford title compound 161 (906 mg, 66% yield) as a light-yellow solid. LRMS (M+1) 496.3 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(C)cc(Br)c1)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(C)cc(N3CCOCC3)c1)N2
Temperature: 120 °C
Yield: 50.9 %

Procedure:
A mixture of 2-(3-bromo-5-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.5 mmol), morpholine (2.2 g, 25 mmol), copper (I) iodide (0.29 g, 1.5 mmol), N,N-dimethylglycine (0.28 g, 2.0 mmol) and potassium carbonate (1.04 g, 7.5 mmol) in DMSO (6 mL) was heated for 4 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.52 g, 51%) as a white solid: LC/MS m/e calcd for C25H32N2O3 (M+H)+: 409.6, observed: 409.2.
Reaction SMILES: [N:1]1[N:2]=[C:3]([NH2:6])[NH:4][CH:5]=1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:28](=O)[CH2:29][CH2:30][CH3:31])[C:23](OCC)=[O:24])=[CH:17][CH:16]=1)#[N:8]>ClC1C=CC(Cl)=CC=1Cl>[O:24]=[C:23]1[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([C:7]#[N:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][CH:17]=2)=[C:28]([CH2:29][CH2:30][CH3:31])[N:2]2[N:1]=[CH:5][N:4]=[C:3]2[NH:6]1
Reactant: Nc1nnc[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Yield: 37.9 %

Procedure:
A solution of 4H-1,2,4-triazol-3-amine (2.4 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (10 g) in 1,2,4-trichlorobenzene (50 mL) was stirred at 180° C. for 6 hr. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (4 g, 38%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:18]=[C:17]([C:19](=[O:24])[NH:20][CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH:21]([NH:20][C:19]([C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:6](=[O:8])(=[O:7])[NH2:5])[CH:18]=1)=[O:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(=O)NC(C)C)cc1S(N)(=O)=O

Procedure:
At room temperature, 19.6 g (0.055 mol) of methyl 2-tert-butylsulfamoyl-4-isopropylcarbamoylbenzoate were stirred in 200 ml of trifluoroacetic acid for 3 h. The mixture was concentrated and the residue was triturated with diethyl ether and filtered off. This gave 15.6 g (95% of theory) of methyl 4-isopropylcarbamoyl-2-sulfamoylbenzoate of m.p. 203-205° C.
Reaction SMILES: C([Li])(CC)C.[CH3:6][O:7][C:8]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:21][S:22]SC>O1CCCC1>[CH3:6][O:7][C:8]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([S:22][CH3:21])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CSSC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Reaction time: 2 h
Yield: 11.1 %

Procedure:
N,N,N′N′-Tetramethylethylendiamine (21 g, 177 mmol) was added drop-wise at −70° C. to a solution of sec-butyllithium (110 mL, 1.4 M in cyclohexane, 154 mmol) in 180 mL tetrahydrofuran. 2-Methoxy-4-trifluoromethyl-benzoic acid (13 g, 59 mmol) in 60 mL tetrahydrofuran was added drop-wise at −70° C. over 2 hours. After complete addition stirring was continued at −70° C. for another 2 hours. Dimethyl disulfide (20 g, 207 mmol) was added at −70° C. within 10 min. Stirring was continued at −70° C. for another hour and the reaction was allowed to warm up. The reaction mixture was quenched with 150 mL water and extracted with 200 mL ethyl acetate. The aqueous phase was adjusted to pH1 by addition of 25% HCl and extracted twice with dichloromethane. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was crystallized with heptane and yielded the title compound as a white solid (1.75 g, 11%), MS: m/e=265.1 [(M−H)−].
Reaction SMILES: CCCC[C:5](=[O:15])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].S(=O)(=O)(O)O>>[CH2:14]([CH:12]1[CH2:11][CH2:10][CH:9]2[CH:14]([C:5](=[O:15])[C:6](=[O:7])[NH:8]2)[CH2:13]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=O)C(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Product: CCCCC1CCC2NC(=O)C(=O)C2C1
Reaction time: 1 h

Procedure:
For example, a solution of 4-n-butylglyoxylanilide (II), (12.2 g, 0.01 mole) is added to concentrated sulfuric acid (23 ml) at 50° C. while maintaining the reaction mixture by cooling below 65° C. The mixture is held at 65° C. for one hour an poured unto ice with stirring. A reddish-orange precipitate is formed and is washed with water. Recrystallization from ethanol yields pure 5-n-butyl-octahydro-2,3-dioxo-1H-indole (III) with mp 112°-113° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:49]=[CH:50][CH:51]=1)[CH2:42][O:43][CH2:44][C:45]#[C:46][CH2:47][OH:48].C(O)C#CCO.COC1C=C(C=CC=1)CBr>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:48][CH2:47][C:46]#[C:45][CH2:44][O:43][CH2:42][C:41]3[CH:49]=[CH:50][CH:51]=[C:39]([O:38][CH3:37])[CH:40]=3)[N:18]=[C:17]([C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(COCC#CCO)c1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: COc1cccc(CBr)c1
Agent: OCC#CCO
Product: COc1cccc(COCC#CCOc2nc(-c3ncccn3)nc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Oc2ccccc2OC)c1
Yield: 25.7 %

Procedure:
Crude 4-tert.-butyl-N-[6-(4-(3-methoxybenzyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was obtained starting from 300 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (Example 5a) and 1096 mg of 4-(3-methoxybenzyloxy)-2-butyn-1-ol (prepared starting from 2-butyn-1,4-diol and 3-methoxybenzylbromide in analogy to a procedure reported in Tetrahedron Lett. 38 (1997), 7887-7890) following the procedure given in Example 91. The compound was purified by column chromatography on silica gel eluting with DCM containing 0-2.5% of methanol followed by chromatography on prep. tlc-plates with DCM containing 5% of methanol. The resulting oil was dissolved in 10 ml of diethyl ether and treated with pentane. The precipitate was collected and dried to give 102 mg of 4-tert.-butyl-N-[6-(4-(3-methoxybenzyloxy)-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide as an almost white powder. LC-MS: tR=5.74 min, [M+1]+=696.40, [M−1]−=694.32.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)[CH2:11][CH2:10]1)=[O:5].[C:40](Cl)(=[O:44])[O:41][CH2:42][CH3:43]>>[CH2:42]([O:41][C:40]([NH:1][C:2]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)[CH2:11][CH2:10]1)=[O:5])=[O:44])[CH3:43]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2nc(N3CCOCC3)nc(N3CCC(CCNC(=O)c4cc(C)ccc4N)CC3)c2cc1OC
Product: CCOC(=O)Nc1ccc(C)cc1C(=O)NCCC1CCN(c2nc(N3CCOCC3)nc3cc(OC)c(OC)cc23)CC1
Temperature: 25 °C

Procedure:
Ethyl chlorocarbonate (10 ml) was added to 540 mg (1.01 mmol) of 4-[2-(2-amino-5-methylbenzoylamino)ethyl]-1-(6,7-dimethoxy-2-morpholino-4-quinazolinyl)piperidine (Compound 1) obtained in Reference Example 13, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, followed by addition of hexane and ether to the residue. The precipitated crystals were collected by filtration to give 430 mg of crude 4-[2-(2-ethoxycarbonylamino-5-methylbenzoylamino)ethyl]-1-(6,7-dimethoxy-2-morpholino-4-quinazolinyl)piperidine, which was then dissolved in 10 ml of ethanol. To the solution was added 210 mg of potassium hydroxide, and the mixture was heated under reflux for one hour. After evaporation of the solvent under reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was washed and dried, and the solvent was evaporated to give 360 mg (overall yield: 64%) of Compound 29 as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.[NH2:23][CH2:24][C@H:25]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([S:46]([NH:49][CH2:50][CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:54])(=[O:48])=[O:47])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[C:26]([O:28][CH3:29])=[O:27]>>[C:57]1([CH2:56][O:55][C:53]([NH:52][CH2:51][CH2:50][NH:49][S:46]([C:43]2[CH:44]=[CH:45][C:40]([C:37]3[CH:38]=[CH:39][C:34]([S:31]([NH:30][C@@H:25]([CH2:24][NH:23][C:20]([C:16]4[CH:15]=[C:14]5[C:19](=[CH:18][CH:17]=4)[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)[N:12]=[CH:13]5)=[O:22])[C:26]([O:28][CH3:29])=[O:27])(=[O:32])=[O:33])=[CH:35][CH:36]=3)=[CH:41][CH:42]=2)(=[O:47])=[O:48])=[O:54])[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: COC(=O)[C@H](CN)NS(=O)(=O)c1ccc(-c2ccc(S(=O)(=O)NCCNC(=O)OCc3ccccc3)cc2)cc1
Reactant: O=C(O)c1ccc2c(cnn2CCCNc2ncccn2)c1
Product: COC(=O)[C@H](CNC(=O)c1ccc2c(cnn2CCCNc2ncccn2)c1)NS(=O)(=O)c1ccc(-c2ccc(S(=O)(=O)NCCNC(=O)OCc3ccccc3)cc2)cc1
Yield: 60.1 %

Procedure:
The product of Example 40, Step B (58 mg, 195 umol) was reacted with the product of Example 44, Step A (144 mg, 205 umol) as in Example 44, Step B and the residue purified by preparative HPLC (Vydac C-18, 21.2 mm×25 cm, 90% acetonitrile/water/0.1% trifluoroacetic acid; 10-70% B over 30 minutes). The product fractions were combined, frozen, and lyophilized to afford the product as a white solid (102 mg, 54%). LRMS (ES): 870.3 ([M+H]+, 100%). 1HNMR (600.1343 MHz, DMSO-d6): 8.52 (d, 1H), 8.51 (s, 1H), 8.29 (d, 1H), 8.17, (d, 1H), 7.82 (m, 9H), 7.74 (d, 1H), 7.64 (d, 1H), 7.49 (b, 1H), 7.31, (m, 6H), 6.61 (t, 1H), 4.98, (s, 2H), 4.46 (t, 2H), 4.19 (dd, 1H), 3.55 (m, 1H), 3.42 (m, 1H), 3.41 (s, 3H), 3.26 (t, 2H), 3.06 (t, 2H), 2.83 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[O:22])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:13]>ClCCl>[CH2:15]([O:14][C:12]([NH:13][C:3]([OH:9])([C:2]([F:10])([F:11])[F:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(O)(NC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (30 g, 176 mmol) in dichloromethane (1 L) was added benzyl carbamate (26.6 g). The reaction mixture was stirred at ambient temperature for 24 h and the resulting precipitate was collected by filtration and dried under vacuum to afford ethyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-hydroxypropanoate (49.0 g, 87% yield), which was used directly without further purification.
Reaction SMILES: [Cl-].[NH4+].[N:3]1([C:9]2[CH:10]=[C:11]([C:18]3[N:23]=[C:22]([C:24]4([OH:28])[CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][CH:19]=3)[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.O>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[C:11]([C:18]2[N:23]=[C:22]([C:24]3([OH:28])[CH2:27][CH2:26][CH2:25]3)[CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:9]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:14]=1
Reactant: O=[N+]([O-])c1cc(-c2cccc(C3(O)CCC3)n2)cc(N2CCOCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccc(C3(O)CCC3)n2)cc(N2CCOCC2)c1
Temperature: 85 °C

Procedure:
Ammonium chloride (22.6 mg, 0.422 mmol) and iron (216 mg, 3.57 mmol) were added to a solution of 1-{6-[3-(morpholin-4-yl)-5-nitrophenyl]pyridin-2-yl}cyclobutanol (250 mg, 0.703 mmol) in ethanol (4.69 mL) and water (2.36 mmol). The reaction mixture was heated to 85° C. for 1 hour, then cooled to room temperature. The reaction was filtered, diluted with water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (7:3 ethyl acetate:hexanes, then 100% ethyl acetate) to afford 1-{6-[3-amino-5-(morpholin-4-yl)phenyl]pyridin-2-yl}cyclobutanol as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.66-7.58 (m, 1H), 7.56 (d, J=7.5, 1H), 7.36-7.23 (m, 2H), 7.01 (s, 1H), 6.90 (s, 1H), 6.34 (s, 1H), 5.81 (s, 1H), 3.90 (m, 4H), 3.23 (m, 4H), 2.64-2.54 (m, 4H), 2.14-2.08 (m, 1H), 1.96-1.92 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[C:13]1([CH3:28])[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=2)[CH:14]=1.O>CN(C)C=O>[CH3:3][C:4]1[N:8]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:15]3[CH:14]=[C:13]([CH3:28])[CH:18]=[CH:17][CH:16]=3)=[CH:27][CH:26]=2)[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: Cc1cccc(Oc2ccc(CBr)cc2)c1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Oc2ccc(Cn3c(C)nc4ccccc43)cc2)c1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of sodium hydride (0.14 g, 3.6 mmole; 62% in oil) in anhydrous dimethylformamide (10 ml), 2-methylbenzimidazole (0.48 g, 3.6 mmole) was added while stirring, and stirring was continued at room temperature for 1 hour. The resultant mixture was cooled to 5°-10° C., and a solution of 4-(3-tolyloxy)benzyl bromide (1.00 g, 3.6 mmole) in anhydrous dimethylformamide (5 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene layer was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 2-methyl-1-[4-(3-tolyloxy)benzyl]benzimidazole (0.84 g) as colorless liquid. nD27.0 1.6112.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16](B4OC(C)(C)CC(C)(C)O4)[CH:15]=[C:14]([NH2:29])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:31]1[CH:32]=[C:33]2[CH:39]=[N:38][N:37]([S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:34]2=[N:35][CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([C:31]4[CH:32]=[C:33]5[CH:39]=[N:38][N:37]([S:40]([C:43]6[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=6)(=[O:41])=[O:42])[C:34]5=[N:35][CH:36]=4)[CH:15]=[C:14]([NH2:29])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)CC(C)(C)OB(c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)O1
Reactant: O=S(=O)(c1ccccc1)n1ncc2cc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 30.2 %

Procedure:
1-(Phenylsulfonyl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-1H-indazol-4-amine (1.5 g, 3.63 mmol), 5-bromo-1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridine (1.350 g, 3.99 mmol), Pd(dppf)Cl2 (0.531 g, 0.726 mmol) and tripotassium phosphate (2.311 g, 10.89 mmol) were divided between 2 microwave vials and dissolved in 1,4-dioxane (18 mL) and Water (6 mL); 9 ml dioxane and 3 ml water in each. Each vial was heated to 100° C. for 10 min in the microwave. Solvent was removed in vacuo and the residue was partitioned between DCM (100 ml) and water (100 ml). The organic layer was collected using a hydrophobic frit and the solvent was removed in vacuo. The residue was taken up in DCM (4 ml) and added to the top of 2×70 g silica SPE cartridges. These were subsequently eluted with 0-100% EtOAc/DCM over 40 mins. The product-containing fractions were combined to give the title compound as a pale yellow solid (581 mg).