Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH2:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH:20][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([C:25]5[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=5)[CH:29]=4)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NCC1(c2nc(-c3ccc(Cl)cc3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3ccc(Cl)cc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 42 %

Procedure:
This compound was synthesized (4-(4-(4-chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 42%). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.99 (d, J=9 Hz, 1H), 7.83 (m, 2H), 7.59 (t, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.42 (t, J=5.4 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 3.99-3.94 (m, 2H), 3.58 (d, J=5.8 Hz, 2H), 3.77-3.71 (m, 2H), 2.35-2.29 (m, 2H), 2.08-2.05 (m, 2H). MS (ESI) m/z: Calculated for C26H20ClF3N4O3S: 548.09. found: 549.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1ccc(N)cc1Br
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-bromo-4-methylaniline to yield 2-[(3-bromo-4-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]1([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28](N(C)OC)=[O:29])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[C:4]1([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]([CH3:1])=[O:29])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CON(C)C(=O)c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of methylmagnesium bromide (980 μL, 1.4 M, 13.8 mmol) in CH2Cl2 (0.5 mL) at 0° C. was added 2-[(S)-1-phenylethylamino]-4-[5-(N-methyl-N-methoxyaminocarbonyl)-benzimidazol-1-yl]pyrimidine (55.4 mg, 0.138 mmol) in CH2Cl2 (1.0 mL) slowly. The reaction mixture was warmed to room temperature slowly and continued stirring for 5 h. The reaction mixture was quenched with saturated aqueous NH4Cl then extracted with CH2Cl2. The combined extracts were washed with brine and dried over Na2SO4. The crude material was purified by preparative thin layer chromatography eluting with 3% MeOH/CH2Cl2 to obtain 38 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.5 (br s, 1H); 8.4 (s, 1H); 8.38 (d, J=5.5 Hz, 1H); 7.93 (br s, 1H); 7.79 (br s, 1H); 7.44-7.28 (m, 5H); 6.74 (d, J=5.2 Hz, 1H); 5.17 (br s, 1H); 2.68 (s, 3H); 1.63 (d, J=6.8 Hz, 3H). Mass spectrum 358.2 (CI, M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[OH:26][C@@H:25]([CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: C1CCNC1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN1CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), and pyrrolidine (60 mg, 0.84 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified on silica gel, gradient elution with dichloromethane, dichloromethane/methanol (95/5), dichloromethane/methanolic ammonia (7M) (98/2 to 90/10), to give (2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (114 mg, 92%).
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>>[NH2:6][C:7]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 247 %

Procedure:
To ice-water bath cooled, conc. H2SO4 (10 mL) was added 2-amino-5-trifluoromethylpyridine (1.70 g, 10.5 mmol). The resulting solution was heated to 50° C. and 69-71% HNO3 (1.7 mL, 2.6 mmol) was added dropwise over 10 min with stirring. The resulting solution was stirred at 80° C. for 46 h, then allowed to cool to room temperature, poured into ice-water (100 mL) and basified to pH 9 with 40% aq NaOH. The resulting mixture was extracted with EtOAc (5×40 mL). The EtOAc solution was dried (MgSO4), and evaporated to give 1.33 g (61%) of 50 as a yellow powder, mp 191°-3° C. 1H NMR (CDCl3), 6.140 (bs, 1H), 7.916 (bs, 1H), 8.590 (s, 1H), 8.670 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4](O)[CH:3]=1.[NH3:13]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:13])[CH:3]=1
Reactant: N
Reactant: Oc1cc(O)c2ccccc2c1
Product: Nc1cc(O)c2ccccc2c1
Temperature: 135 °C
Reaction time: 14 h

Procedure:
A solution of 1,3-dihydroxynaphthalene (1, 50 g, 0.312 mol) in liquid ammonia (200 mL) at −78° C. was sealed in a 1 L steel bomb containing a glass liner. The reaction mixture was warmed to 135±10° C. and 1300 psi for 14 h with vigorous stirring. The vessel was allowed to cool to 60° C., and the ammonia was released slowly. The remaining traces of ammonia were removed by co-evaporation with THF (2×150 mL) under a stream of argon at 60° C. The intermediate 4-hydroxy-2-naphthylamine (2) was not isolated but was immediately converted to the di-tert-butyloxycarbonyl protected compound 3. A solution of di-tert-butyl dicarbonate (175 g, 0.801 mol) in dry THF (300 mL) and N,N-diisopropylethylamine (140 mL, 0.803 mol) were sequentially added to the bomb. The bomb was re-sealed, and the contents were warmed at 100° C. with stirring for 4 h. The bomb was cooled to room temperature, opened, and the residue partitioned between saturated aqueous NaCl (800 mL) and ethyl acetate (500 mL). The aqueous phase was extracted with ethyl acetate (200 mL×2). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Chromatography on silica gel (1:8 to 1:4 ethyl acetate/hexane) and recrystallization with ethyl acetate/ethanol/hexane provided pure 77.41 g (69%) of the title compound (3). 1H NMR (CDCl3, 400 MHz) 8.14 (d, 1H, J=8.1 Hz), 7.66 (d, 1H, J=8.1 Hz), 7.43 (dd, 1H, J=6.8, 8.2Hz), 7.35 (dd, 1H, J=6.8, 82 Hz), 7.22 (d, 1H, J=1.8 Hz), 7.15 (br, 1H, NH), 6.69 (s, 1H), 1.59 (s, 9H), 1.37 (s, 9H); 13C NMR(CDCl3) 153.71, 152.9, 136.11, 135.20, 128.12, 128.01, 126.81, 126.03, 123.61, 107.94, 102.95, 82.98, 82.10, 28.93, 27.69; MS m/z 382.52 (M+Na)+.
Reaction SMILES: [H+].[B-](F)(F)(F)F.[CH3:7][N:8]1[CH:12]([CH3:13])[CH2:11][CH2:10][C:9]1=[NH:14].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]=[C:24]=[O:25]>C1C=CC=CC=1>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[C:17]=1[NH:23][C:24]([N:14]=[C:9]1[CH2:10][CH2:11][CH:12]([CH3:13])[N:8]1[CH3:7])=[O:25]
Reactant: CC1CCC(=N)N1C
Reactant: Cc1cccc(C)c1N=C=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: c1ccccc1
Product: Cc1cccc(C)c1NC(=O)N=C1CCC(C)N1C
Reaction time: 2 h

Procedure:
The HBF4 salt of 1,5-dimethyl-2-iminopyrrolidine (6.75 g.; 0.0337 mole) is converted to free base in benzene in the usual manner. Then 4.96 g. (0.0337 mole) of 2,6-dimethylphenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo leaving an oily residue which eventually crystallizes. Recrystallization from ethyl acetate gives the product, 1-(2,6-dimethylphenyl)-3-(1,5-dimethyl-2-pyrrolidylidene)urea, m.p. 120°-122° C.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[C:18](#N)C>>[CH3:18][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CC#N
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Product: Cc1nsc2nc3ccccc3n12
Yield: 88 %

Procedure:
2-Butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (1.00 g, 4.04 mmol) was refluxed in 100 mL acetonitrile for 18 h. The solvent was then evaporated and the residue was recrystallized from methanol to give 0.671 g (88%) of the title compound: mp 192°-193° C.; 1H NMR (CDCl3) δ7.81 (dm, 2H), 7.47 (td, 1H), 7.34 (td, 1H), 2.92 (s, 3H) ppm; IR (KBr) ν1564, 1481, 1453, 1430, 1304, 1208, 756, 745 cm-1 ; MS m/z 189 (M+), 148 (M+ -CH3CN).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:27]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)=[CH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:29]1([CH:28]=[C:27]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:24][O:23][C:22]([CH3:25])([CH3:26])[O:21]4)[CH:18]=[C:13]3[CH:12]=2)[C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC1(C)OCC(Cc2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OCC(Cc2cnc3[nH]c(C(=CC4CCCC4)c4ccc(S(C)(=O)=O)cc4)cc3c2)O1
Yield: 88.6 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (460 mg, 0.74 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 mL, 4 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL) and then washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (315 mg, 88.5%) as a light yellow solid: LC/MS m/e calcd for C27H32N2O4S [M+H]+ 481.63, observed 481.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>CCOC(C)=O>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2-hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (0.8 g; 3.6 mmol) in EtOAc (15 ml) at 0° C. is added NEt3 (610 μl) and methanesulfonyl chloride (340 μl). After addition the mixture is warmed to RT and stirred for 3 days. After completion the reaction mixture is acidified with diluted hydrochloric acid and extracted twice with EtOAc. The organic phase is washed with brine, dried over MgSO4 and evaporated to give methanesulfonic acid 2-tert-butoxycarbonylamino-benzyl ester (0.73 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([NH:20][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Reaction time: 3 h
Yield: 92.4 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and after 220 mg (2.1 mmol) of benzylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 375 mg (yield: 94.5%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:4]=1.[CH2:16]([N:18]1[C:22]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:21][NH:20][C:19]1=[S:28])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:15][C:9]1[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=1[C:5]1[N:4]=[C:3]([CH2:2][S:28][C:19]2[N:18]([CH2:16][CH3:17])[C:22]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[N:21][N:20]=2)[O:7][N:6]=1
Reactant: Fc1ccc(F)c(-c2noc(CCl)n2)c1
Reactant: CCn1c(-c2cccs2)n[nH]c1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(SCc2nc(-c3cc(F)ccc3F)no2)nnc1-c1cccs1
Yield: 49.3 %

Procedure:
5-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole (23 mg, 0.10 mmol) and 4-ethyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione (23 mg, 0.11 mmol) was dissolved in anhydrous DMF (1 ml) and potassium carbonate (21 mg, 0.15 mmol) was added. After stirring for 22 h ethyl acetate was added, the resulting mixture was washed twice with water and once with brine, dried over MgSO4 and evaporated. Flash chromatography using heptane:ethyl acetate 1:1 yielded the title compound (20 mg, 50%). 1H NMR (CDCl3) d (ppm): 7.64 (m, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.10 (m, 3H), 4.70 (s, 2H), 4.08 (q, 2H), 1.32 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22]CC2C=CC=CC=2)[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH3:5]>C1COCC1.CO.[Pd]>[OH:22][C:20]1[CH:19]=[C:9]([CH:8]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 70 h
Yield: 94.7 %

Procedure:
To a solution of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (7.07 g) in THF (50 mL) and methanol (50 mL) was added 10% palladium on carbon (727 mg) as a slurry in THF (1 mL) and methanol (1 mL). The mixture was placed under vacuum and stirred under an atmosphere of hydrogen for 70 hours. The mixture was filtered through diatomaceous earth, and the diatomaceous earth washed with methanol (2×100 mL), followed by evaporation in vacuo. The residues were dissolved in ethyl acetate (10 mL), treated with isohexane (40 mL), the solid filtered off and washed with isohexane (50 mL) to afford the desired compound (5.17 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:11][CH3:12].[CH2:13]([O:15][CH:16]([O:19]CC)[CH:17]=[CH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][CH2:18][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:11][CH3:12])[CH3:14]
Reactant: C=CC(OCC)OCC
Reactant: CCc1cc(C#N)cc(C)c1Br
Product: CCOC(=O)CCc1c(C)cc(C#N)cc1CC

Procedure:
The title compound is prepared from 4-bromo-3-ethyl-5-methyl-benzonitrile and commercially available acrolein diethyl acetal following literature procedures (G. Battistuzzi, S. Cacchi, G. Fabrizi, R. Bernini, Synlett 8 (2003) 1133-1136); LC-MS: tR=0.91 min; 1H NMR (CDCl3): δ 1.2 (m, 6H), 2.38 (s, 3H), 2.44 (m, 2H), 2.70 (q, J 7.5 Hz, 2H), 3.03 (m, 2H), 4.18 (q, J 7.3 Hz, 2H), 7.30 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:17]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19].CN1CCOCC1>C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:17]([N:12]2[C:13]3[C:9](=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:29][CH:28]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CCS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(=O)(=O)CC)cccc21
Reaction time: 0.5 h

Procedure:
Ethanesulfonyl chloride (0.26 g, 2 mmol) was added to a stirred solution of methyl 2-(4-amino-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (0.58 g, 1.7 mmol), as described in Example 3 Step B, and 4-methylmorpholine (0.25 g, 2.5 mmol) in DCM (8 mL) at 0° C. After 30 min, an additional portion of ethanesulfonyl chloride (0.1 g, 1 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE: EA=2:1) to afford the title compound. LC/MS m/z=435.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].CCN(CC)CC>C1COCC1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH:7]=[CH:6][CH:5]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from 4-(3-amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 70) by treatment with methanesulfonyl chloride and Et3N in THF at 23° C. Obtained as a light yellow solid (24 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:25].[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][S:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)Cc2ccccc2F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(Cc1ccccc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
After dissolving 690 mg of 1-(tert-butoxycarbonyl)-4-(2-fluorobenzylsulfonyl)piperidine in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered out to obtain the title compound (517 mg, 91% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.C([Li])CCC.[Cl:23][C:24]1[S:25][C:26]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=1>C1COCC1.O>[Cl:23][C:24]1[S:25][C:26]([C:29]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:34])[C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=1
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: O=C(c1ccc(Cl)s1)C(F)(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1ccc(Cl)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
To a chilled (−78° C.) stirred solution of 1.5 g (5.0 mmol) of 5-bromo-1-(4-fluorophenyl)-1H-indazole in THF was added 2.0 mL (5.0 mmol) of n-butyllithium dropwise followed by 1.0 g (4.6 mmol) of 2-chloro-5-trifluoroacetylthiophene in one portion. After 30 minutes, the mixture was diluted with 10 mL of water, warmed to room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate-hexanes (gradient 10-30%) to afford 300 mg (15.5%) of the title compound. MS m/z 427.82 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH3:16])=[N:11][CH:12]=[C:13]([CH3:15])[N:14]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH3:16])=[N+:11]([O-:25])[CH:12]=[C:13]([CH3:15])[N:14]=1
Reactant: Cc1cnc(C)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c[n+]([O-])c(C)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 45 °C

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine at 0° C. in dioxane was added mCPBA (750 mg). The reaction mixture was heated at 45° C. for 3 h. The reaction was diluted with CH2Cl2, washed with NaHCO3 dried (MgSO4), filtered, and concentrated. It was used without purification: 1H NMR (CDCl3) δ 2.30, 2.54, 7.33, 7.42, 7.54, 8.13; 13C NMR (CDCl3) δ 14.04, 21.85, 128.10, 130.12, 131.64, 132.14, 134.07, 135.23, 136.44, 141.66, 153.87, 154.24.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([CH2:43][CH2:44][OH:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:40]5[CH2:41][CH2:42][N:37]([CH2:43][CH2:44][OH:45])[CH2:38][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: OCCN1CCNCC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(CCO)CC1
Yield: 12.8 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.427 mmol) and 2-piperazin-1-yl-ethanol (0.161 mL, 1.317 mmol) were reacted in the manner described in Example 36. 1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea (33 mg, 13%) was isolated as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (brs, 1H), 9.25 (brs, 1H), 8.52 (s, 1H), 7.55 (s, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.40 (s, 1H), 4.30 (m, 2H), 3.95 (s, 3H), 3.45 (m, 2H), 2.85-2.30 (m, 12H), 1.25 (m, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:11])[C:3]=1[O:12][CH3:13].OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([O:12][CH3:13])[C:4]=1[I:11])[CH3:20]
Reactant: COc1c(Br)ccc(C(=O)O)c1I
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(OC)c1I

Procedure:
A mixture of 4-Bromo-2-iodo-3-methoxy-benzoic acid (12.0 g, 0.0336 mol) and conc.H2SO4 (20 mL) in EtOH (200 mL) is refluxed overnight. After reaction, evaporated out EtOH and the mixture is extracted with ethyl acetate (3×1000 mL). The combined organic phase is washed with water and brine, dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate=20:1 to afford the desired product as a colourless oil.