Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:36][CH:35]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5cccc(CN(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
175 a) A suspension of [3-(bromomethyl)phenyl]boronic acid (1.0 g, 4.6 mmol), N-methyl-methanesulfonamide (0.56 g, 5.1 mmol) and potassium carbonate (1.9 g, 14 mmol) in acetone (10 mL) was stirred for 6 hours at room temperature. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated under reduced pressure. Crude (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid was isolated as a yellow viscous oil (1.08 g, 88%). MS=266 (M+Na)+. 175 b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid (650.0 mg, 2.674 mmol) in a manner analogous to Example 2c. Product isolated as a pale yellow foam (0.331 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 7.99-7.95 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.84 (s, 3H). MS=351 (MH)+. 175 c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzyl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.214 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (24.0 mg, 0.0439 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.007 g, 6%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.55-7.46 (m, 3H), 7.42 (d, J=7.4 Hz, 1H), 7.00-6.91 (m, 3H), 6.65 (s, 3H), 4.42 (s, 2H), 3.19-3.14 (m, 4H), 2.87 (s, 3H), 2.83 (s, 3H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS=506 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]([F:31])([F:30])[S:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([S:22][C:21]([F:31])([F:20])[F:30])=[CH:24][CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1ccc(SC(F)(F)F)cc1
Product: Fc1cnc(Nc2ccc(SC(F)(F)F)cc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-(trifluoromethylthio)aniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.73 (s, 1H), 9.47 (s, 1H), 8.13 (d, 1H, J=3.6 Hz), 7.79 (d, 2H, J=9.0 Hz), 7.51 (d, 2H, J=9.0 Hz), 7.28 (d, 1H, J=2.1 Hz), 7.12 (dd, 1H, J=2.4 and 9.0 Hz), 6.83 (d, 1H, J=8.7 Hz), 4.23 (s, 4H);
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Br:24][C:20]1[CH:21]=[C:22]([F:23])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:27]([NH2:28])=[O:29])=[C:10]([NH:9][C:8]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:7])[S:14][N:13]=2)=[C:18]([F:26])[C:19]=1[F:25]
Reactant: NCCCCN1CCCC1
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)c(F)c2F)nsc1NC(=O)Oc1ccccc1
Product: NC(=O)c1c(OCc2c(F)cc(Br)c(F)c2F)nsc1NC(=O)NCCCCN1CCCC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,3,6-trifluoro-benzyloxy)4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. MS (APCI, m/z): 550 and 552 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2([C:10]#N)[CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.[Li]CCCC.C1C[O:23]CC1>>[Br:1][C:2]1[CH:13]=[C:12]2[C:5]([CH2:6][C:7]3([CH2:9][CH2:8]3)[C:10]2=[O:23])=[CH:4][CH:3]=1
Reactant: N#CC1(Cc2ccc(Br)cc2I)CC1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=C1c2cc(Br)ccc2CC12CC2
Temperature: -78 °C
Yield: 51 %

Procedure:
A dried flask was charged with 1-(4-bromo-2-iodobenzyl)cyclopropanecarbonitrile (Intermediate 51, 3.29 g, 9.09 mmol) and dry THF (30 mL) was added under argon atmosphere. The resulting mixture was cooled to −78° C. and n-BuLi (2.5 M in hexanes, 7.27 mL, 18.2 mmol) was added dropwise. The solution was allowed to reach r.t. The reaction was quenched with MeOH (2 mL) and HCl (1M, 5 mL). The mixture was extracted with EtOAc. The water phase was basified with sat NaHCO3 and extracted with EtOAc twice. The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo. HCl (1 M, 4 mL) and DCM (5 mL) were added and the organic phase was collected. This was repeated twice. The water phase was basified with sat NaHCO3 and extracted with DCM. The combined organic phases were dried through a phase separator and evaporated to dryness to give the title compound (1.1 g, 51% yield): MS (CI) m/z 237 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([F:37])[CH:36]=2)=[C:27]([CH3:38])[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([F:37])[CH:36]=2)=[C:27]([CH3:38])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Br)ccc1-c1cncc(F)c1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)ccc1-c1cncc(F)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 3-(4-bromo-2-methyl-phenyl)-5-fluoro-pyridine (Intermediate 12) in analogy to Example 1a): MS (ISP): 489.2 and 491.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[N:25][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: Cc1c2n(c3c(-c4ccc(N(C)C)nc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (77 mg, 87%), MS (ISP) m/z=355.5 [(M+H)+], mp 248° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 6-dimethylamino-pyridin-3-ylboronic acid (53.9 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N)c3)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a microwave vial was added 0.032 gm (0.075 mM) 1-[2-(3-Amino-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one followed by 0.75 ml of 1M tetrabutylammonium fluoride in THF. The vial was sealed and placed in a 80° C. oil bath for two hours then stirred at room temperature overnight. The mixture was diluted with 10 ml ethyl acetate, rinsed (3×50 ml) water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. Purification on a preparative silica gel thin layer chromatography plate (5/95 MeOH/CH2Cl2) gave 0.014 gm (64% yield) of 1-[2-(3-Amino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one, M+1 295, M.P. 239-241° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:29]2[CH2:30][CH:31]([C:33]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)=[O:34])[CH2:32]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(C1CNC1)N1CCCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CCCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 35.9 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidin-3-ylpyrrolidin-1-ylmethanone (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) to afford 348 as a white foam (50 mg, 37%). LCMS (Method G): RT=5.81 min, M+H+=516. 1H NMR (CDCl3, 400 MHz) δ 8.08 (m, 1 H); 7.71 (m, 1 H); 7.26 (m, 2 H); 4.35 (m, 4 H); 3.89-3.83 (m, 9 H); 3.66 (m, 2 H); 3.55-3.43 (m, 5 H); 3.31 (m, 2 H); 2.94 (s, 3 H) and 1.98-1.81 (m, 4 H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10]C(=O)OC(C)(C)C)=[N:7][C:8]=1[CH3:9].N1C(C)=CC(C)=CC=1C.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]1[CH2:39][C:40]1[O:44][C:43]([C:45](O)=[O:46])=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[NH2:10][C:6]1[N:7]=[C:8]([CH3:9])[C:3]([CH2:2][NH:1][C:45]([C:43]2[O:44][C:40]([CH2:39][N:30]3[CH:31]=[CH:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:28])=[CH:41][CH:42]=2)=[O:46])=[C:4]([CH3:18])[CH:5]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1ccc(Cn2ccc3ccccc3c2=O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: Cc1cc(N)nc(C)c1CNC(=O)c1ccc(Cn2ccc3ccccc3c2=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 5-(aminomethyl)-4,6-dimethylpyridin-2-ylcarbamate (41.1 mg, 0.163 mmol) in THF (5 ml) were added collidine (0.022 ml, 0.163 mmol), 5-((1-oxoisoquinolin-2(1H)-yl)methyl)furan-2-carboxylic acid (44.0 mg, 0.163 mmol) and HATU (81.0 mg, 0.212 mmol). After stirring for 18 h at rt, all volatiles were removed in vacuo. The crude intermediate was purified by column chromatography (CombiFlash Companion, 12 g SiO2, heptane to EA), dissolved in DCM (1 ml) and TFA (1 ml), kept for 1 h at rt, and concentrated. Purification by preparative HPLC (Waters Sunfire Prep C18 OBD 5 um, 100×19 mm, A: H2O+0.1% TFA, B: MeCN+0.1% TFA, 6-36% B in 10 min, 30 ml/min, rt) afforded the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.37 (s, 3H), 4.28 (d, 2H), 5.23 (s, 2H), 6.45 (d, 1H), 6.62 (s, 1H), 6.68 (d, 1H), 7.06 (d, 1H), 7.49-7.59 (m, 4H), 7.65-7.76 (m, 2H), 8.21 (d, 1H), 8.52 (t, 1H), 13.33 (s, 1H). LCMS RtM=1.50 min, [M+H]+=403.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[F:13].[ClH:15].CO>[Pd].CO>[ClH:15].[NH2:10][C:6]1[C:5]([F:13])=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(N)c1F
Yield: 85 %

Procedure:
2-Fluoro-3-nitrobenzoic acid methyl ester (9.10 g, 0.046 mol), 10% hydrochloric acid/methanol (25 ml), methanol (60 ml), and 5% palladium/carbon (50% wet product) (2.7 g) were introduced, and the reaction mixture was hydrogenated at room temperature. After completion of the reaction, the catalyst was filtered away, and the filtrate was concentrated under reduced pressure. The concentration residue was washed with diisopropyl ether, as a result of which 8.01 g (yield: 85%) of the indicated compound was obtained.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+]>C(O)C>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:8]3[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][N:7]=3)=[O:22])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:26][CH:25]=1
Reactant: Nc1ccc(S)cc1
Reactant: CC(C)(C)c1cnc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cnc(NC(=O)c2ccc(Sc3ccc(N)cc3)c([N+](=O)[O-])c2)s1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A mixture of the product of Example 161A (500 mg, 1.472 mmol), 4-aminothiophenol (350 mg, 2.796 mmol) and anhydrous sodium acetate (604 mg, 7.36 mmol) in anhydrous ethanol (15 mL) was heated at reflux under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature and the ethanol removed by rotary evaporation. The residue was partitioned with water (50 mL) and ethyl acetate (100 mL), and the organic phase washed with water (2×50 mL) and brine (50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration of the solid with 4% ethyl acetate/methylene chloride (25 mL) afforded the title compound (452 mg, 72%).
Reaction SMILES: [OH:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5][CH2:4][CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5][CH2:4][CH2:3]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCC(O)c2ccccc2N1
Product: CC(=O)OC1CCCC(=O)Nc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 6-hydroxy-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)one (9.2 g) in acetic anhydride (200 ml) is maintained at 80° C. for 3 hours. The reaction mixture is cooled to room temperature and the solvents removed under reduced pressure. Ether (300 ml) is added, and their resulting solution washed with water (150 ml) and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 6-acetoxy-3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].C([Li])(C)(C)C.ClC[C@@H](O)[CH2:33][N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CO>[CH2:42]([N:34]([CH2:33][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: -30 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) was added to 8 mL of methanol. The solution was cooled to −30° C. under the protection of nitrogen flow and then the methanol solution containing 1 mmol of tert-butyl lithium was added. The mixture was stirred at −78° C.˜−20° C. for 2 hours. (S)-1-chloro-3-(dibenzylamino)propan-2-ol (0.29 g, 1 mmol) was added and then the mixture was heated slowly to 100° C. and stirred for 2 hours. After the solution was cooled down, saturated ammonium chloride solution and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to provide 0.31 g of white solid in 65% yield. HPLC: 99.2%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(Cl)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (182 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (286 mg).
Reaction SMILES: NC(N)=O.CO[CH:7]([O:28]C)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH2:26][NH2:27])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.[C:30]([C:34]1[CH:38]=[C:37]([NH:39][C:40](=O)[O:41]CC(Cl)(Cl)Cl)[N:36]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[C:30]([C:34]1[CH:38]=[C:37]([NH:39][C:40]([NH:27][CH2:26][C:20]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=2[O:18][C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[N:9]([CH2:8][CH2:7][OH:28])[N:10]=[CH:11]3)=[O:41])[N:36]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: COC(Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21)OC
Agent: NC(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Temperature: 80 °C

Procedure:
Preparation of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(241-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorobenzyl)urea 70: (2-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorophenyl)methanamine (2.00 g, 5.791 mmol), 2,2,2-trichloroethyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (3.516 g, 8.686 mmol) and N,N-diisopropylethylamine (3.026 mL, 17.37 mmol) were suspended in N,N-dimethylacetamide (50 mL) and heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue diluted with EtOAc and saturated aqueous NH4Cl. The organics were washed with water (3×), brine, dried (MgSO4) and then concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant 35-45% EtOAc/Hexanes). After evaporation of the solvent, the desired product was obtained as a pale yellow foam (2.57 g, 74%). MS (APCI+) m/z 602 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.43 (d, 1H, J=9 Hz), 6.72-7.30 (m, 9H), 6.18 (s, 1H), 6.01 (br, 1H), 5.47 (t, 1H, J=6.1 Hz), 4.76 (t, 1H, J=5.3 Hz), 4.44 (t, 4H, J=5.6 Hz), 3.38 (s, 6H), 2.37 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=O>CN(C1C=CN=CC=1)C.ClCCl>[C:21]([C:26]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17](=[O:19])[CH3:18])=[CH:3][C:2]=2[N:1]=1)([CH3:25])([CH3:22])[CH3:20]
Reactant: CC(=O)Nc1ccc(NCC2CCCCC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCCCC1

Procedure:
Following the same procedure of Example 6, a mixture of N-{3-amino-4-[(cyclohexylmethyl)amino]phenyl}acetamide (1.57 g, 6.0 mmol) (for preparation see in Example 6, step D) and DMAP (0.15 g, 1.2 mmol) in dichloromethane (70 mL) was treated with trimethylacetyl choride (0.83 g, 6.6 mmol) at −10° C. After evaporation of the solvent, the residue was dissolved in 1,2-dichloroethane (40 mL) and then divided into eight Teflon-capped test tubes. The vessels were irradiated by microwave for 2 h at 170° C. After purification by MPLC (EtOAc as eluent on silica gel), the desired title compound was obtained as a white solid (1.42 g, 72%). 1H NMR (400 MHz, CD3OD): δ 1.24 (m, 5H), 1.64 (m, 2H), 1.67 (s, 9H), 1.70 (m, 1H), 1.77 (m, 2H), 2.12 (m, 1H), 2.18 (s, 3H), 4.45 (d, J=7.62 Hz, 2H), 7.50 (m, 1H), 7.84 (d, J=8.98 Hz, 1H), 8.43 (d, J=1.95 Hz, 1H). MS (ESI) (M+H)+: 328.3. Anal. Calcd for C20H29N3O+1.20 TFA+0.30H2O (469.71): C, 57.28; H, 6.61; N, 8.95. Found: C, 57.34; H. 6.67; N, 8.85.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
Compound 4 was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (M1) (306 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (162 mg). MS (ISP) 425.4 [(M+H)+]; mp 204° C.