Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.C([O:25][C:26](=[O:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)C.ClCCl.C(=O)([O-])[O-].[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]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:30]=[N:29][N:28]([CH2:27][C:26]([OH:42])=[O:25])[CH:32]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Temperature: 85 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.20 g, 0.44 mmol), ethyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate (Aldrich, Cat. No. 683566) (0.14 g, 0.49 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (18 mg, 0.022 mmol), and potassium carbonate (0.184 g, 1.33 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was degassed and recharged with nitrogen three times. The reaction mixture was stirred at 85° C. for 6 h. The reaction mixture was adjusted to pH˜4 with 1N HCl. The precipitates formed were filtered, washed with water and ether, and dried under vacuum to afford the desired product (0.10 g, 50%). LCMS (M+H)+=448.0/450.0.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(OCl)(C)(C)C.C([O:18][C:19](=O)[CH2:20][S:21][CH3:22])C.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:22][S:21][CH:20]1[C:9]2[C:2](=[CH:3][CH:4]=[C:5]([C:6]#[N:7])[CH:8]=2)[NH:1][C:19]1=[O:18]
Reactant: CCOC(=O)CSC
Reactant: N#Cc1ccc(N)cc1
Agent: CC(C)(C)OCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2ccc(C#N)cc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-amino-benzonitrile (84.64 mmoles) in DCM (200 ml) under a nitrogen atmosphere, at −78° C., there is added, dropwise, tBuOCl (84.64 mmoles) dissolved in 20 ml of DCM and then, after 10 minutes, ethyl(methylsulphanyl)acetate (84.64 mmoles) dissolved in 20 ml of DCM is added dropwise to the reaction mixture. After stirring for one hour at −78° C., triethylamine (0.152 mol) is added dropwise. The reaction mixture is stirred at ambient temperature for one hour. Water is added and the phases are then separated. The organic phase is washed with water and then with saturated aqueous NaCl solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The residue is taken up in ethyl ether and aq. 2M HCl solution is added. After stirring overnight, the yellow precipitate is filtered off and dried in vacuo to yield the title product, which is used directly in the next reaction.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[N:16]([CH3:27])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:18]=[N:17][N:16]([CH3:27])[C:15]=2/[CH:14]=[CH:13]/[C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][N:9]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(F)cc2)c1/C=C/c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of lithium hydroxide monohydrate (34 mg, 0.8 mmol) in water (1.0 mL) was added dropwise to a suspension of 6-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-nicotinic acid methyl ester (136 mg, 0.4 mmol) in THF (1.0 mL) and methanol (0.2 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (114 mg, 87%) as a white solid. MS: m/e=323.2 [M−H]−.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)C=O.[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][O:31]/[N:32]=[C:33](/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)\[CH2:34][CH2:35][C:36]([OH:38])=O)=[CH:28][CH:27]=1>O1CCCC1>[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:15][C:14]=1[CH2:24][O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][O:31]/[N:32]=[C:33](/[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)\[CH2:34][CH2:35][C:36]([NH2:8])=[O:38])=[CH:28][CH:27]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (10 ml) and added dropwise to a mixture of a 25% aqueous ammonia (15 ml) and ethyl acetate (20 ml) at 0° C. After stirring at room temperature for 1 hour, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyramide (315 mg, yield 45%) as colorless crystals. m.p. 164-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]C)=O)[NH:9]2)=[CH:5][CH:4]=1.[NH3:16]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH2:16])=[O:14])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: N
Product: COc1ccc2cc(C(N)=O)[nH]c2c1
Temperature: 50 °C

Procedure:
A suspension of 4 g (19.49 mmol) of methyl 6-methoxy-2-indolecarboxylate in 60 ml of 28% aqueous ammonia is heated at 50° C. for 14 h in an autoclave. After filtration of the mixture over sintered glass, the white solid obtained is washed with water and dried, and is then added to a hot mixture of ethyl acetate/cyclohexane (100 ml/10 ml). The medium is cooled in a water/ice bath and filtered over sintered glass, to give 1.05 g of 6-methoxy-1H-indole-2-carboxamide in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[S:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH3:1][C:2]1([CH3:11])[S:7][CH2:6][CH2:5][N:4]([S:22]([C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)(=[O:24])=[O:23])[CH:3]1[C:8]([OH:10])=[O:9]
Reactant: CC1(C)SCCN[C@H]1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc3ccccc3c2)C1C(=O)O

Procedure:
Following typical sulfonylation conditions and method L, the title compound is prepared from (S)-2,2-dimethyl-thiomorpholine-3-carboxylic acid and naphthalene-2-sulfonyl chloride. LCMS (m/z): 381.2 (M+1), 379.3 (M−1), CHN: Calc CHN: 53.66, 5.30, 7.36. Found CHN: 593.51, 5.20, 7.07.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][NH2:11].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][NH:11][C:15]1[C:16]([Cl:20])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1ccc(Br)c(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CNc2nc(Cl)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 1-(2-bromo-5-methoxyphenyl)methanamine (3.6 g, 13 mmol) and 2,4,5-trichloropyrimidine (1.60 mL, 14 mmol) in N,N-dimethylformamide (41.3 mL) was added potassium carbonate (5.53 g, 40 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product as a light yellow gel (4.65 g, 96%). LCMS for C12H10BrCl2N3O (M+H)+: m/z=361.9, 363.9.
Reaction SMILES: CO[C:3](=[O:15])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[CH3:16][NH:17][CH2:18][CH2:19][NH:20][CH3:21]>>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([CH3:21])[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:3]1=[O:15]
Reactant: COC(=O)C(Br)c1cccc([N+](=O)[O-])c1
Reactant: CNCCNC
Product: CN1CCN(C)C(c2cccc([N+](=O)[O-])c2)C1=O

Procedure:
1,4-Dimethyl-3-(3-nitro-phenyl)-piperazin-2-one was prepared from bromo-(3-nitro-phenyl)-acetic acid methyl ester and N,N′-dimethyl-ethane-1,2-diamine in an analogous manner to Example 1072b. Product isolated as a clear-orange oil (959 mg, 98%). LCMS (m/e) 250 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.32 (s, 1H), 8.14 (d, 1H, J=8.2 Hz), 7.76 (d, 1H, J=7.6 Hz), 7.54-7.46 (m, 1H), 3.83 (s, 1H), 3.83-3.73 (m, 1H), 3.26-3.18 (m, 1H), 3.08-3.01 (m, 1H), 2.97 (s, 3H), 2.79-2.69 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]3[N:36]([CH3:37])[CH:35]=[CH:34][C:21]3=[N:22][C:23]=2[C@@H:24]([NH:26]C(=O)OC(C)(C)C)[CH3:25])[CH2:13]1>Cl.O1CCOCC1>[NH2:26][C@H:24]([C:23]1[N:22]=[C:21]2[CH:34]=[CH:35][N:36]([CH3:37])[C:20]2=[CH:19][C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:13]1)[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1N1CCCC(N2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of tert-butyl ((1S)-1-(6-(3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (100 mg, 0.59 mmol) in HCl/dioxane (10 mL) was stirred at 20° C. for 2 hours. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give title diastereomers. Peak 2 (longer retention time, 20 mg, 18% yield): 1H NMR (400 MHz, CD3OD) δ ppm 7.90-7.98 (m, 1H), 7.68-7.77 (m, 4H), 7.40 (d, J=3.0 Hz, 1H), 6.50 (d, J=3.1 Hz, 1H), 5.07 (q, J=6.6 Hz, 1H), 4.04-4.16 (m, 1H), 3.75 (s, 3H), 3.59-3.74 (m, 3H), 2.79-2.94 (m, 1H), 2.21-2.32 (m, 1H), 1.82-2.13 (m, 3H), 1.69 (d, J=6.8 Hz, 3H); ESI-MS m/z [M+H]+ calc'd for C23H25N5O2, 404. found 404. Peak 1 (shorter retention time, 30 mg, 27% yield): 1H NMR (400 MHz, CD3OD) δ 7.85 (s, 1H), 7.64-7.57 (m, 4H), 7.32-7.26 (m, 1H), 6.35 (d, J=2.4 Hz, 1H), 5.29 (q, J=6.9 Hz, 1H), 4.20-4.08 (m, 1H), 3.85-3.70 (m, 2H), 3.67 (s, 3H), 3.45 (ddd, J=5.1, 7.4, 9.0 Hz, 1H), 2.95-2.86 (m, 1H), 2.34-2.22 (m, 1H), 2.12-2.00 (m, 2H), 1.82 (qd, J=8.5, 12.2 Hz, 1H), 1.65 (d, J=6.8 Hz, 3H); ESI-MS m/z [M+H]+ calc'd for C23H25N5O2, 404. found 404.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:15](O)=[O:16]>O>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH:15]=[O:16])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=CO
Solvent: O
Product: CCCCc1ccc(NC=O)c([N+](=O)[O-])c1
Yield: 69.2 %

Procedure:
4-n-Butyl-2-nitroaniline (25-g; 0.13 mole) and formic acid (25 g; 0.54 mole) were mixed together at laboratory temperature and the mixture was then refluxed for forty minutes. After cooling to laboratory temperature the clear solution was poured into water (500 ml) and the orange solid which separated was filtered off, washed with water, dried and crystallised from light petroleum (b.p. 60°-80° C.) to give 5-n-butyl-2-formamido-1-nitrobenzene (20 g), m.p. 72°-73° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[C:20]#[N:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br.O>CN(C)C=O>[C:20]([C:19]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:3][CH2:4]1)#[N:21]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](N)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](N3CCCCC3)CC2)c1

Procedure:
A mixture of ethyl 3-[(trans-4-aminocyclohexyl)amino]-4-cyanobenzoate (0.490 g, 0.96 mmol), potassium carbonate (0.66 g, 4.78 mmol) and 1,5 dibromopentane (0.130 mL, 0.96 mmol) was stirred in dimethylformamide (10 mL) at room temperature for 48 h. Water (20 mL) was then added to the mixture, and the water phase was extracted with dichloromethane (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using methanol in dichloromethane (5% to 10%) to afford ethyl 4-cyano-3-[(trans-4-piperidin-1-ylcyclohexyl)amino]benzoate (0.145 g, 43% yield). MS (EI) for C21H29N3O2: 356 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][O:18][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C(CO)NCCCOc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.08 h
Yield: 37.1 %

Procedure:
A solution of 645 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydroxyacetamide in 2 ml of N,N-dimethylformamide was added under ice cooling to a suspension of 84.3 mg of sodium hydride in 1 ml of N,N-dimethylformamide, and the mixture was stirred for 5 minutes. Then, a solution of 299.3 mg of methyl iodide in 1 ml of N,N-dimethylformamide was added dropwise under ice cooling, and the mixture was stirred for 10 minutes. After the stirring, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified by TLC (developing solvent: chloroform/methanol=19/l) to afford 250 mg of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]methoxyacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[O:6][CH2:7][CH2:8][N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH2:22][C:10]1=2.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>Cl.CO>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[O:6][CH2:7][CH2:8][N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:10]1=2
Reactant: COc1cccc(OCCn2c3c(c4ccccc42)CCN(C(=O)OC(C)(C)C)CC3)c1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: COc1cccc(OCCn2c3c(c4ccccc42)CCNCC3)c1
Temperature: 50 °C

Procedure:
A mixture of tert-butyl 6-[2-(3-methoxyphenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.447 g, 1.02 mmol) in methanolic hydrochloric acid was warmed in a 50° C. bath for 1.5 h. The mixture was evaporated, taken up in ethyl acetate, then washed with 1 N sodium hydroxide. The organic phase was dried and evaporated to provide an oil. The oil was diluted with methanol and a solution of maleic acid in methanol was added. Evaporation and crystallization of the residue from methanol, ethyl acetate, and hexanes, afforded 0.347 g of the title compound (mp=131-133° C.).
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]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[O:29][N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c2cc1OC
Yield: 29 %

Procedure:
The title compound was prepared as described in Example 113C with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) and phenyl 3-tert-butylisoxazol-5-ylcarbamate from the previous step (118 mg, 0.45 mmol) to give 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (41 mg, 29%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.04 (s, 1H), 8.57 (s, 1H), 7.59-7.56 (m, 2H), 7.44-7.39 (m, 2H), 7.30 (d, 1H), 6.98 (d, 1H), 6.04 (s, 1H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 464 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([C:17]3[CH:18]=[CH:13][N:14]=[C:15]([NH:19][CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)[N:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1F
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(F)c(F)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 6,7-difluoro-1H-indole and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM-protecting group with TBAF. Yield: 100 mg (27%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>C(Cl)(Cl)Cl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 133.6 %

Procedure:
To a suspension of 2-amino-5-methoxybenzamide (2.42 g, 14.6 mmol) and pyridine (6 mL) in CHCl3 (120 mL) was added 3-nitrobenzoyl chloride (3.0 g, 16.1 mmol). The resulting mixture was stirred at RT for 6 h. The volatiles were removed in vacuo and the resultant solid was washed with Et2O to give the 5-Methoxy-2-(3-nitrobenzoyl)aminobenzamide (6.15 g) which was taken directly on to the next step. HPLC retention time 6.58 mins.
Reaction SMILES: C(OC([NH:8][CH:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=O)(C)(C)C.[NH2:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24]>>[NH2:8][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:17]([NH:20][C@@H:21]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:22]([OH:28])[C@H:23]([CH:25]1[CH2:27][CH2:26]1)[OH:24])=[O:19]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccn1)C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Product: NC(Cc1ccccn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of N-(tert-butoxycarbonyl)-3-(pyridin-2-yl)-D,L-alanine [J. Gen. Chem. USSR, 40, 2488 (1970)1 and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by acidic hydrolysis there were obtained (S or R)-α-amino-N-[(1S,2R,3 S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyridin-2-yl)propionamide, MS: 267 (M+H)+, and (R or S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyridin-2-yl)propionamide, MS: 267 (M+H)+, each as a colourless foam.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:26][C:27]3[N:32]=[C:31]([C:33](OC)=[O:34])[CH:30]=[CH:29][CH:28]=3)=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[OH:2][NH:3][C:33]([C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][C:15]2[C:14]3[C:18](=[CH:19][C:11]([O:10][CH3:9])=[CH:12][CH:13]=3)[NH:17][C:16]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:32]=1)=[O:34]
Reactant: [NH3+]O
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(Cc3cccc(C(=O)NO)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 92.8 %

Procedure:
To a solution of hydroxylammonium chloride (373 mg) in dimethylsulfoxide (2.7 mL) was added sodium hydrogen carbonate (541 mg), and this mixture was stirred at 50° C. for 70 minutes. Then, methyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (200 mg) was added thereto, followed by stirring at 50° C. for 3 days. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (186 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.38 (2H, s), 6.63 (1H, dd, J=2.3, 8.5 Hz), 6.87 (1H, d, J=2.3 Hz), 7.15 (1H, dd, J=1.5, 7.3 Hz), 7.29-7.39 (2H, m), 7.42-7.53 (2H, m), 7.59-7.70 (2H, m), 7.70-7.81 (2H, m), 9.13 (1H, s), 11.10 (1H, s), 11.18 (1H, s). ESI-MS (m/z): 374 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC[C@H]1CO1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.C(N)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Solvent: C1CCOC1
Solvent: CC(C)N
Product: COc1ccc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 120.6 %

Procedure:
A mixture of (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 mmol), (prepared as described for the starting material in Example 269), and isopropylamine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2R)-7-(2-hydroxy-3-isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (243 mg, 84%).