Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:38][N:39]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cnc(N)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine (75 mg, 0.337 mmol). The final product was collected as a white solid (87 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.78 (s, 2H) 8.59 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.11 (s, 1H) 7.82 (s, 1H) 6.87 (s, 2H) 5.91 (s, 1H) 5.14 (quin, J=6.57 Hz, 1H) 4.42 (s, 1H) 4.41 (s, 1H) 2.52-2.57 (m, 2H) 2.13 (s, 3H) 1.51-1.58 (m, 2H) 1.50 (s, 3H) 1.49 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=460.7
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].[O:25]1CCN(CCOC2C=CC(C(N)CCC)=CC=2)CC1>>[C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:23][CH2:24][O:25][CH2:22][CH2:21]2)=[CH:15][CH:16]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2]
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Reactant: CCCC(N)c1ccc(OCCN2CCOCC2)cc1
Product: CCCC(NC(=O)CC#N)c1ccc(OCCN2CCOCC2)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 29 except that 1-(4-(2-morpholinoethoxy)phenyl)butan-1-amine (28) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-amine (25). This produced a crude product which was purified by flash silica gel column chromatography, eluting with 4:96 mixture of methanol/dichloromethane, to give 32 (370 mg, 76%) as a clear oil: MS (ES+) m/z 346.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:6][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH2:4][C:2](=[O:1])[CH3:3]
Reactant: c1ccccc1
Reactant: CC(=O)C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CC(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 74 %

Procedure:
Mesityl oxide (5.9 g, 60.2 mmol) was added drop-wise to a solution of aluminum chloride (10.3 g, 77.4 mmol) in 100 mL of benzene at 0° C. After stirring and warming up to room temperature for 4 h, the mixture was poured to 100 mL of ice-water mixture, extracted with diethyl ether (3×15 mL), and washed with saturated sodium bicarbonate (1×15 mL) and brine (1×15 mL). After the extract was dried (MgSO4) and concentrated at reduced pressure, high-vacuum distillation of the crude afforded the title compound (7.8 g, 74% yield) as a colorless oil:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-].[Na+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COC(=O)Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 110 °C
Yield: 98.1 %

Procedure:
A solution of methyl 2-(4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)acetate (1.3799 g, 3.54 mmol) in tetrahydrofuran (THF) (8 mL) and water (2 mL), was prepared and treated with sodium hydroxide (1.063 mL, 10.63 mmol). The reaction was then heated by microwaves to 110° C., for 30 minutes. After cooling, crude material from a test of the above reaction run on a smaller scale (˜40 mg) was combined with this mixture. The combined solution was then neutralised with 2M HCl and diluted with further water and ethyl acetate. The product was extracted into the organic phase and the organics separated (hydrophobic frit) then concentrated in vacuo to provide 1.3033 g of desired material. LCMS (M+1) 376, RT 1.24 mins.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[N:14]=2)=[CH:5][CH:4]=1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(Nc2nc3cc([N+](=O)[O-])ccc3o2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Nc2nc3cc(N)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 mL of methanol was slowly added dropwise to the compound (b) prepared in Preparation 2 (1.31 mmol, 1 eq) and 5% Pd/C (0.4 g), and then the reaction mixture was charged with hydrogen and stirred at room temperature for 24 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:31])([CH3:32])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:42][S:39]([CH:36]5[CH2:38][CH2:37]5)(=[O:41])=[O:40])=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(N2CCN(c3cccc(C4Nc5ccc(C(=O)O)cc5CC4(C)C)c3)CC2)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cccc(C4Nc5ccc(C(=O)NS(=O)(=O)C6CC6)cc5CC4(C)C)c3)CC2)c(C)c1
Yield: 24.9 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol), 4-dimethylaminopyridine (39 mg, 0.32 mmol), cyclopropane sulfonamide (76 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid (2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amide (30 mg, 25%) as a light yellow solid: LC/MS m/e calcd for C33H40N4O3S (M+H)+: 573.8, observed: 573.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15]OS(C)(=O)=O)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:25]#[N:26].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:25]#[N:26])[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CC#N)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 135 °C

Procedure:
A mixture of 2.04 g of 4(S)-(3-methanesulfonyloxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 2.17 g of sodium cyanide in 12 ml of dimethylsulfoxide is heated to 135° C. for 15 hours. The mixture is cooled to room temperature and diluted with water and ethyl acetate. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.32 (1:1 EtOAc-heptane); Rt=4.82 (gradient I).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17]>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:19]([N+:16]([O-:18])=[O:17])[CH3:20])=[CH:5][CH:4]=1
Reactant: CC[N+](=O)[O-]
Reactant: CSc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CSc1ccc(C=C(C)[N+](=O)[O-])cc1

Procedure:
A stirred solution of 4-methylsulfanyl-benzaldehyde (5.0 g, 28.8 mmol) and ammonium acetate (0.666 g, 8.6 mmol) in nitroethane (17 ml, 236 mmol) is heated at reflux for 5 hours. The solvent is removed and the residue is dissolved in CHCl3 (100 ml) and washed with water (100 ml) followed by brine (100 ml). After drying (MgSO4) the solvent is removed to give the title compound as a yellow solid which is used crude in the next step.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](F)[N:29]=4)[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:35])=[O:5])[CH2:3][CH2:2]1.[CH3:36][O-:37].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:37][CH3:36])[N:29]=4)[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:35])=[O:5])[CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: C[C@H]1CCc2c(ccc(-c3cnn(C4CCNCC4)c3)c2Oc2cccc(F)n2)N1C(=O)C1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(Oc2c(-c3cnn(C4CCNCC4)c3)ccc3c2CC[C@H](C)N3C(=O)C2CC2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-cyclopropyl(5-(6-fluoropyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.024 g, 0.05 mmol), and sodium methoxide (0.015 g, 0.28 mmol) in N,N-dimethylformamide (1 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (16% to 34% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-cyclopropyl(5-(6-methoxypyridin-2-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.0033 g, 13%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.79-0.87 (m, 1H), 0.91-1.00 (m, 2H), 1.10-1.18 (m, 4H), 1.39-1.49 (m, 1H), 1.79-1.84 (m, 2H), 1.97-2.09 (m, 3H), 2.18-2.41 (m, 2H), 2.62-2.79 (m, 3H), 3.12-3.19 (m, 2H), 3.62 (s, 3H), 4.15-4.27 (m, 1H), 4.72-4.89 (m, 1H), 6.41 (t, J=8.00 Hz, 2H), 7.36 (d, J=8.40 Hz, 1H), 7.55-7.65 (m, 2H), 7.79 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 488 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][CH:13]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:14][CH:15]=[CH2:16])=[CH:10][CH:9]=1.B.CSC.C1C[O:34]CC1>CCOCC>[OH:34][CH2:16][CH2:15][CH2:14][CH:13]([C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[O:12][C:11]1[CH:25]=[CH:26][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1
Reactant: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Reactant: C1CCOC1
Agent: B
Solvent: CCOCC
Solvent: CSC
Product: N#Cc1ccc(C(CCCO)Oc2ccc(OC3CCCCO3)cc2)cc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
4-{1-[4-(Tetrahydro-2H-pyran-2-yloxy)phenoxy]-3-butenyl}benzonitrile (4.6 g, 13 mmol; from step (d) above) was dissolved in dry THF (50 mL) under argon and cooled to −5° C. Borane-methylsulfide complex (BH3×SMe2) (3.5 mL of a 2 M solution in ether) was added dropwise at 0 to 5° C. The mixture was stirred at that temperature for 1.5 h. After 4 h at rt, tlc showed that the reaction was complete. The reaction mixture was quenched with 14 mL of H2O and 5 g of NaBO3. The mixture was stirred overnight, the solvent decanted off, and the residue treated with ether and decanted. The combined organic fractions were washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by chromatography on silica (iso-propanol:ethyl acetate:heptane; 5:20:70). Yield: 2.44 g (58%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:4]=2[CH2:3]1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1>C1COCC1.[Pd].Cl>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:13][C:10]2[CH:11]=[CH:12][C:4]3[CH2:3][C:2]([CH3:16])([CH3:1])[O:7][B:6]([OH:8])[C:5]=3[CH:9]=2)=[O:30])=[C:27]([C:34]([F:35])([F:36])[F:37])[CH:26]=1
Reactant: CC1(C)Cc2ccc([N+](=O)[O-])cc2B(O)O1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)Cc2ccc(NC(=O)c3ccc(F)cc3C(F)(F)F)cc2B(O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3,3-dimethyl-7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (80 mg, 0.36 mmol) in dry THF (8 mL) was passed through a Thales Nano H-Cube hydrogenator (10% Pd/C catalyst, 1 mL/min flow rate, 1 atm, 30° C.), flushing with an additional 2 mL of THF. To the reaction solution was then added an excess of triethylamine (0.3 mL) and 4-fluoro-2-trifluoromethylbenzoyl chloride (100 mg, 0.44 mmol). The reaction was stirred at room temperature for 16 hours, and then diluted with aqueous hydrochloric acid (10 mL, 1 M). After vigorous mixing, the mixture was extracted with EtOAc (3×5 mL). The combined organic portions were dried over magnesium sulfate and concentrated to dryness. The crude product was purified by silica gel chromatography to produce the title compound as a white solid. LCMS (M/Z): 382 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (s, 6H) 2.83 (s, 2H) 7.14 (d, J=8.4 Hz, 1H) 7.55-7.73 (m, 2H) 7.71-7.86 (m, 2H) 7.90 (d, J=2.3 Hz, 1H) 8.35 (s, 1H) 10.47 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:26])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 358.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([F:30])=[CH:18][N:17]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]2[C:19]([F:30])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=4[CH:14]=3)[N:21]=2)=[CH:28][CH:27]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)cc1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)cc4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 5-amino-2-methoxycarbonylbenzofuran with 2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gave N4-(4-chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine. 1HNMR (DMSO-d6): δ10.28 (bs, 1H), 10.18 (bs, 1H), 8.25 (d, 1H, J=4.5 Hz), 7.96 (bs, 1H), 7.84 (m, 1H), 7.67 (m, 3H), 7.57 (m, 1H), 7.37 (bd, 2H, J=9.0 Hz), 3.88 (s, 3H); LCMS: purity: 96%; MS (m/e): 413 (MH+).
Reaction SMILES: C[CH:2]([O:6][C:7]([CH3:9])=[O:8])COC.[C:10]([O-])(=O)C(C)=C.[OH:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C(O)=O>>[CH3:2][O:6][C:7](=[O:8])[CH:9]=[CH2:10].[OH:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COCC(C)OC(C)=O
Reactant: C=C(C)C(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: OC=Cc1ccccc1
Product: C=CC(=O)OC

Procedure:
The same procedure as described in Example 3 was employed in this example. Specifically, about 100 g of PGMEA solution containing 25 wt. percent of methacrylate-hydroxystyrene copolymer (CMM, 50/50, from Maruzen) was added in with about 35 mg of oxalic acid and 11.4 g of MOCH. The reaction was quenched with 4 g of basic active aluminum oxide and showed 41 mole % protection on the phenol groups of the PHS polymer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]([NH2:13])=[O:12])[CH2:5]2.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22].O>C(Cl)Cl>[C:21]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][CH:6]1[C:11]([NH2:13])=[O:12])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: NC(=O)C1Cc2cc(F)ccc2N1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(F)cc2CC1C(N)=O
Reaction time: 6 h
Yield: 75.6 %

Procedure:
To a mixture of intermediate (17) (0.0094 mole) in DCM (30 ml), cooled in an ice bath under argon, was added triethylamine (0.031 mole) followed by acetyl chloride (0.031 mole). The resulting mixture was allowed to return to room temperature. After stiffing for 6 hours, the mixture was cooled in an ice bath and 50 ml of water was added. The mixture was allowed to stir about 20 minutes, was filtered and the solid was allowed to dry to obtain 1.58 g of 1-acetyl-5-fluoro-2,3-dihydro-1H-indole-2-carboxamide (intermediate 18, mp. 232-235° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.CN(C)C=O.[CH2:25]([O:27][CH2:28][CH2:29][NH2:30])[CH3:26]>O>[NH2:12][C:4]1[N:3]=[C:2]([NH:30][CH2:29][CH2:28][O:27][CH2:25][CH3:26])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: CCOCCN
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCCNc1nc(N)nc2c1CCCC2
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 32.4 %

Procedure:
To a mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (100 mg, 0.545 mmol), triethylamine (221 mg, 2.18 mmol) and dimethylformamide (2 ml) was added ethoxyethylamine (98 mg, 1.10 mmol) at room temperature. After the mixture was stirred for 2.5 hours at 90° C., the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo. The residue was purified by preparative TLC (10% MeOH/CHCl3) to give the object compound (41.7 mg, 32.4%).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[CH:6][CH:5]=1>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([NH:2][CH3:1])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 20 h

Procedure:
40 mL liquid methylamine was added to a stirred mixture of N-(4-bromo-phenyl)-4-fluoro-3-nitro-benzamide (1.5 g, 4.4 mmol) in a pressure tube. The mixture was stirred for 20 h at 60° C. The mixture was cooled and concentrated i.vac. The residue was taken up in ethyl acetate, filtered with celite and silica gel and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.B(F)(F)F>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C@H:7]2[C@H:7]([C:6]3[CH:9]=[CH:10][CH:3]=[CH:4][CH:5]=3)[N:20]2[S:17]([C:14]2[CH:13]=[CH:12][C:11]([CH3:21])=[CH:16][CH:15]=2)(=[O:18])=[O:19])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C=O)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: COc1ccc([C@H]2[C@H](c3ccccc3)N2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
4-Methoxybenzaldehyde (1.22 ml, 10 mmol) and p-toluenesulphonamide (1.71 g, 10 mmol) were refluxed in toluene (70 ml) for 5 minutes using a Dean and Stark apparatus. Reflux was maintained while BF3 (C2 H5)2O (0.05 ml, 0.4 mmol) was added via a syringe. The reaction mixture was maintained at reflux for 12 hours before being allowed to cool to room temperature whereby the title compound precipitated from the toluene. Filtration followed by recrystallisation from dichloromethane-petrol yielded N-(4-methoxybenzylidene)-toluene-p-sulphonamide as a yellow solid (0.478 g; 17%) m.p. 127° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
30 g of 3,5-dinitro-4-phenoxy-benzoic acid in 200 ml of methanol are combined with 3 ml of concentrated sulphuric acid and the whole is boiled for 3 hours under reflux. After evaporation of the solvent, the residue is dissolved in ethyl acetate, and traces of unreacted acid are destroyed with dilute sodium bicarbonate solution. After drying of the ethyl acetate solution, the solvent is eliminated by evaporation, the residue is recrystallised from ethyl acetate/methanol. The desired ester melting at 171°-173° C is obtained with a very good yield.
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[C:12]2=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:15][N:11]2[C:10]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([N+:28]([O-])=O)[C:21]=2[CH3:31])=[N:9]1)(=[O:7])[CH3:6].[H][H]>[Ni].C1COCC1>[C:5]([N:8]1[C:12]2=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:15][N:11]2[C:10]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([NH2:28])[C:21]=2[CH3:31])=[N:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)n1nc(-c2c(C)cc(C)c([N+](=O)[O-])c2C)n2nc(C(C)(C)C)cc12
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)n1nc(-c2c(C)cc(C)c(N)c2C)n2nc(C(C)(C)C)cc12
Yield: 92.5 %

Procedure:
Acetic acid (0.5 ml) was added to Raney nickel (8 spoon-spatulas full) and after washing with THF the catalyst was added to the product of part (a) (16.6 g, 44.9 mmole) in THF (160 ml). The resulting mixture was shaken in an atmosphere of hydrogen at atmospheric pressure for 4 hours and then filtered, the catalyst washed with THF and the filtrate evaporated to give a solid (14.1 g). This material was chromatographed on a dry deactivated silica gel column eluting with 1% ethyl acetate in methylene chloride to give the partially hydrated product, m.p. 206°-207° C., 12.7 g (83%).