Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(OC(F)(F)F)cc1
Product: O=[N+]([O-])c1cc(F)ccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At −10° C., 90% fuming nitric acid (25 mL) was added to concentrate sulfuric acid (50 mL) slowly to keep the temperature below 0° C. At −20° C., 1-fluoro-4-trifluoromethoxy-benzene (5 g, 27.7 mmol) was added portionwise to keep the temperature of the reaction mixture below 0° C. After addition, the reaction mixture was kept at 0° C. for 30 min, poured into ice-water, extracted with EtOAc. The extracts were concentrated to give a mixture (6.05 g) of 4-fluoro-2-nitro-1-trifluoromethoxy-benzene and 1-fluoro-2-nitro-4-trifluoromethoxy-benzene in a 3:1 ratio. The crude nitration product (6.05 g) was dissolved in ethanol (40 mL) and shacked with 10% Pd/C (310 mg) and concentrate HCl (2.8 mL) under H2 (50 psi) for 3.5 h. Filtration and concentration gave a mixture (8.0 g) of 5-fluoro-2-trifluoromethoxy-phenylamine and its isomer 2-fluoro-5-trifluoromethoxy-phenylamine in 3:1 ratio. Without purification, the phenylamines (7 g, 35.8 mmol) were suspended in dichloromethane (100 mL), treated with trifluoroacetic anhydride (71 mmol) and triethylamine (20 mL) for 16 h. The reaction mixture was washed with saturated NaHCO3 and brine. The organic phase was further purified by silica gel chromatography (hexane/EtOAc 9:1) to give a mixture (5.29 g) of 2,2,2-trifluoro-N-(5-fluoro-2-trifluoromethoxy-phenyl)-acetamide and its isomer in 1:4 ratio, which was nitrated in a same procedure as the first step. The nitrate (3 g) was heated under reflux with morpholine (10 mL) in 1,2-dichloroethane (30 mL) for 3 h. Evaporation to remove excess morpholine. The residue was diluted with dichloromethane, washed with HCl (0.5N, 100 mL). The organic phase was purified by FC (hexane/EtOAc 7:3 to 1:1) to give the title compound 5-morpholin-4-yl-4-nitro-2-trifluoromethoxy-phenylamine (2.48 g). LC-MS: m/e=306.1 (M−H), 308.2 (M+H). 1H-NMR (500 MHz, CDCl3): 8.04 (s, 1H), 6.35 (s, 1H), 4.54 (br. s, 1H), 3.90 (t, 4H), 3.07 (t, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>CO.CCOC(C)=O.[Pd]>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(-c2cccnc2)cc1
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of 3-pyridylboronic acid (500 mg, 4.06 mmol), 1-iodo-4-nitrobenzene (1.01 g, 4.06 mmol) and Pd(Ph3P)2Cl2 (140 mg, 0.199 mmol) in dioxane (15 mL), a solution of Na2CO3 (1.00 g, 9.43 mmol) in H2O (10 mL) was added. The mixture was stirred at 100 C for 2 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column on ISCO, eluted with 20-100% EtOAc in hexanes to give 3-(4-nitrophenyl)pyridine as a solid (487 mg). A mixture of 3-(4-nitrophenyl)pyridine (487 mg, 2.43 mmol) and Pd—C(10%, 80 mg) in MeOH (25 mL) and EtOAc (5 mL) was hydrogenated under balloon H2 for 5 h. The mixture was then filtered through celite. The filtrate was concentrated in vacuo to give 4-(pyridin-3-yl)aniline as a solid (403 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@@](F)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 2,2,2-trifluoroethylamine, the title compound was prepared in the same manner as described for example 1c. Colorless, viscous oil (73%). MS: m/e=558(M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N:16]=[C:17]=S)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([NH2:37])[C:24]([NH2:36])=[CH:25][C:26]=1[N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][N:33]([CH3:35])[CH3:34]>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:36][C:24]3[CH:25]=[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][CH:28]4[CH2:32][N:33]([CH3:35])[CH3:34])[C:21]([Cl:20])=[CH:22][C:23]=3[N:37]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CC1CCCN1c1cc(N)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Solvent: CN(C)C=O
Product: CN(C)CC1CCCN1c1cc2[nH]c(Nc3cc(CNC(=O)OC(C)(C)C)ccc3Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(4-Chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (68 mg, 0.2 mmol) followed by TEA (160 μL, 1.2 mmol) were added to 4-chloro-5-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzene-1,2-diamine (95 mg) in DMF (3 mL). The mixture was stirred at rt for 4 h and then purified by chromatography to give the sub-title compound.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C(N)(CO)CO>C(#N)C>[CH3:17][O:16][C:14](=[O:15])[CH2:13][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][O:1]2
Reactant: COC(=O)CBr
Reactant: Oc1cccc2c1CCCO2
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1cccc2c1CCCO2
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A solution of chroman-5-ol (2.1 g, 14 mmol), methyl bromoacetate (1.6 mL, 16.8 mmol), and cesium carbonate (6.8 g, 21 mmol) in 50 mL acetonitrile was heated at 60° C. for 3 hours. PS-Trisamine scavenger resin was then added to the warmed solution followed by an additional 30 minutes heating. The reaction mixture was then cooled and filtered. The filtrate was collected, diluted with 100 mL ether, washed with brine (1×50 mL), dried (Na2SO4), and the solvent removed in vacuo to give 2.1 g (68%) of the title compound, pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 6.92 (t, 1H, J=8.3 Hz), 6.33 (d, 1H, J=8.3 Hz), 6.31 (d, 1H, J=8.3 Hz), 4.72 (s, 2H), 4.02 (t, 2H, J=5.1 Hz), 3.64 (s, 3H), 2.56 (t, 2H, J=6.6 Hz), 1.83 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)NCC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97 %

Procedure:
To 4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (1.0 g, 3.09 mmol) was added ethyl chloroformate (15 mL) and the reaction mixture is allowed to reflux for 18 h. The reaction mixture is then concentrated to dryness yielding 1.05 g (97%)product.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:19]([O:21][CH2:22][CH2:23]O)[CH3:20].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:20][CH2:19][O:21][CH2:22][CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CCOCCO
Reactant: O=C(O)Cc1ccc(NCC2C=CCCC2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)Cc1ccc(NCC2C=CCCC2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(cyclohex-2-enylmethylamino)phenylacetic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-(cyclohex-2-enylmethylamino)phenylacetate.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:60]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:67][CH:60]3[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: NC1CCCCCC1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NC2CCCCCC2)cc1Cl
Reaction time: 8 h
Yield: 38.6 %

Procedure:
In THF (30 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(3-chloro-4-methoxybenzylamino)-pyrimidine-5-carboxylic acid (202 mg, 0.54 mmol) and DIEA (0.3 mL, 1.78 mmol). The reaction mixture was cooled in an ice bath, then HATU (250 mg, 0.65 mmol) and cycloheptanyl amine (67 mg, 0.60 mmol) were added. The react ion was conducted at ambient temperature overnight. The reaction mixture was concentrated, quenched with water and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=3/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-meth oxybenzyl)amino)-N-cycloheptanylpyrimidine-5-formamide (98 mg, 38.6% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:19][S:20]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[O:11][S:20]([CH3:19])(=[O:22])=[O:21])(=[O:22])=[O:21]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.3 %

Procedure:
(1R,2S)-1-Amino-2-hydroxyindan (3.0 g, 20mmol) was dissolved in dry THF (40 ml) and triethylamine (8.4 ml, 60.0 mmol) at 10° C. Methane sulphonyl chloride (5.0 g, 44.0 mmol) dissolved in THF (10 ml) was added at such a rate that the internal temperature remained below 15° C. Following the addition the mixture was stirred at room temperature for 20 hours and then evaporated. To the residue was added EtOAc (100 ml) and the mixture washed with saturated aqueous sodium bicarbonate and then water. The organic solution was dried over magnesium sulphate and evaporated to give (1R,2S)-1-methanesulphonamido-2-methylsulphonyloxyindan (5.7 g, 93%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][N:15]([CH3:28])[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:28])[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](/[CH:26]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:26]/[C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]([N:15]([CH3:14])[CH3:28])=[CH:17][CH:18]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)=[CH:18][CH:17]=1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: Cc1ccc2c(c1)O/C(=C\c1ccc(N(C)C)c3ccccc13)C(=O)/C(=C/c1ccc(N(C)C)c3ccccc13)O2

Procedure:
Calone is reacted with 4-dimethylaminonaphthalene-1-carbaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(4-dimethylaminonaphthalen-1-yl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4)CC3)c(OC)nc2c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 91.5 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.27 (s, 4H), 3.76 (s, 4H), 3.89 (s, 3H), 4.12 (s, 3H), 6.87-6.96 (m, 3H), 7.13 (s, 2H), 7.29-7.31 (m, 2H), 7.72-7.75 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][N:30]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: COc1ccc(C(=O)O)nc1
Product: COc1ccc(C(=O)Nc2ccc(F)c([C@]3(C)CCOC(N)=N3)c2)nc1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 5-methoxy-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [C:1]1(=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C>[Pd].C(O)C>[CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1C=C1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccccc1CC1CCCCC1

Procedure:
1-(Cyclohexylidenemethyl)-2-nitrobenzene (3.45 g), prepared as above, glacial acetic acid (30 mL), ethanol (50 mL), and a catalytic amount of 10%Pd/C were shaken on a Parr Hydrogenator under a atmosphere of hydrogen at 23° C. for 24 h. The mixture was filtered through clay and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10% EtOAc/hexanes to give 2-(cyclohexylmethyl)aniline.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH2:41][CH2:42][CH3:43])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol) and 1-iodobutane (14.0 μl, 0.12 mmol) to yield the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[C:5](=[CH:13][C:14]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[O:15])[NH:4][C:3]1([CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([S:44]([N:10]2[CH2:11][CH2:12][CH:8]([CH2:7][N:6]3[C:2](=[O:1])[C:3]([CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)([CH2:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[NH:4][C:5]3=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[O:15])[CH2:9]2)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCN(S(=O)(=O)c3ccccc3)C2)cc1

Procedure:
According to the procedure of Example 13, the title compound of 46B (100 mg, 0.20 mmol) and benzenesulfonyl chloride (0.04 ml, 0.198 mmol) were reacted to generate the title compound of Example 46 as a white solid (25 mg, 0.037 mmol, 37% yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11](=O)[NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:11]([CH2:10][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:14]([OH:16])=[O:15])#[N:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(CC#N)C(=O)O
Temperature: 23 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
20.0 g (86 mmol, 1 equiv.) of Boc-L-asparagine was dissolved in 120 mL of dry pyridine and 20.0 g (97 mmol, 1.3 equiv.) of dicyclohexylcarbodiimide dissolved in 60 mL of dry pyridine was added dropwise over a period of 30 minutes. The reaction was stirred for 3 hours at 23° C. and filtered through a 2 μm nylon filter. The filtrate was concentrated in vacuo on a rotary evaporator and 100 mL of water was added. The pH was adjusted to 10 with 40% NaOH (aq.) and the solution filtered through a 2 μm nylon filter once again. The filtrate was passed through a 120 mL bed of Dowex 50X8-400 ion exchange resin and the resin washed with four column volumes of 1:1 methanol:water. The filtrate was concentrated in vacuo to yield 17.5 g (95% yield) of the title compound as a white solid. 1H-NMR (CD3OD): 4.40 p.p.m (m, 1H); 2.95 p.p.m. (m, 2H); 1.40 p.p.m. (s, 9H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@@H:26]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 2-methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (0.203 g, 0.74 mmol) and (S)-1-phenylethylamine (0.15 mL, 1.16 mmol) in 2 mL of xylenes was heated to 100° C. After 8 h, the reaction mixture was concentrated and purified by chromatography (silica, 1:1 hexanes: EtOAc, then 1:1 CH2Cl2: EtOAc) to give 0.133 g of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.49 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.83 (d, J=8.0 Hz, 1H); 7.3-7.5 (m, 8H); 6.79 (d, J=5.5 Hz, 1H); 5.75 (br s, 1H); 5.21 (br s, 1H); 1.65 (d, J=6.9 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2Cl.[NH3:15]>[Cl-].[NH4+]>[OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:15]
Reactant: CC(O)Cn1cnc2c(Cl)ncnc21
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)Cn1cnc2c(N)ncnc21

Procedure:
9-(2-Hydroxy-1-propyl)-6-chloropurine (I, 9 g, 42.5 mmol) was dissolved in saturated methanolic ammonia and ammonium chloride (50 mg). The mixture was heated at 130° in a bomb for 6 hr. The resulting solution was evaporated to dryness and recrystallized from ethanol/acetone. Yield=6.68 g of a colorless crystalline product (81%); mp 193°-194°; uv (H2O; pH 5.5); λmax 260 nm; TLC in CHCl3 :MeOH (5:1); Rf 0.44.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][OH:22])=[C:15]([Cl:23])[N:14]=1)(=[O:11])=[O:10].O1CCC[CH2:25]1>[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][O:22][CH3:25])=[C:15]([Cl:23])[N:14]=1)(=[O:11])=[O:10]
Reactant: C1CCOC1
Reactant: COc1nc(CO)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Product: COCc1nc(OC)c(NS(=O)(=O)c2cccc(Cl)c2Cl)nc1Cl
Reaction time: 20 h

Procedure:
To a stirred solution of 2,3-dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide (Example 127) (0.1 g) in tetrahydrofuran (3 mL) was added manganese dioxide (0.131 g) and the resulting suspension was stirred for 20 h, filtered and concentrated. The residue was taken up into methanol (3 mL) and acetic acid (0.1 mL). To this solution was added ethylamine hydrochloride (0.081 g) and sodium cyanoborohydride (0.051 g). The resulting mixture was stirred for 20 h and concentrated onto silical gel (1 g) and eluting with methanol/dichloromethane mixtures to afford the titled compound (0.029 g) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1>C1COCC1>[O:25]=[C:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[CH:27][CH:26]=3)=[O:15])=[CH:17][CH:18]=2)[NH:22]1
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCOC1
Product: O=C1Cc2ccc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
A dry 25 mL flask was charged with Thiophene-2-carbonyl chloride (0.756 g, 5.16 mmol) and THF (10 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.02 g, 3.98 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure Thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.924 g, 2.53 mmol, 64%).