Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)([C:14]([NH2:16])=[O:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:9]2[NH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)([C:14]([NH2:16])=[O:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 2 h

Procedure:
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (0.040 g, 0.13 mmol) was dissolved in methanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (20 mg, 0.2 mmol). The reaction vessel was charged to 50 PSI with hydrogen and shaken for 2 h. The reaction mixture was then filtered and concentrated to give crude 5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide as a glass (0.040 g. 100%). LCMS calculated for C14H15N4O2 (M+H)+: m/z=271.1. found: 271.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[O:25])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g) in tetrahydrofuran (10 mL)-ethanol (5 mL) was gradually added sodium borohydride (0.040 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methanol as colorless crystals (0.47 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 113-114° C.
Reaction SMILES: [C:1]1([C:7]([C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:9][CH2:8][C:7]([C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C)(C(=O)C2CCCCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Phenyl-3-cyclohexanecarbonyl-butan-1-al (57.8 g, 224 mmol) was dissolved in methylene chloride (1650 mL) followed by addition of 1-(2-methoxyphenyl)piperazine hydrochloride (56.3 g, 246 mmol). Acetic acid (41 mL) may optionally be added to turn the slurry into a solution. To the stirred solution, sodium triacetoxyborohydride (60.3 g, 284 mmol)was slowly added. A slight exotherm resulted and a slurry was produced. The reaction mixture was stirred for an additional 3 hours at room temperature. The reaction was then quenched by addition of 2.0 N sodium hydroxide (1050 mL) producing a pH of about 10 for the quenched reaction mixture. The mixture was then extracted with methylene chloride (2 times, 1 L and 300 mL). The organic extracts were combined, washed successively with 1.0 N HCl (600 mL), 1.0 N sodium hydroxide (600 mL), brine (600 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the final title compound as a thick oil;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][C:11]2=[N:10]1.P(Br)(Br)([Br:21])=O>ClCCCl.C(Cl)Cl>[Br:21][C:13]1[C:12]2=[CH:18][N:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[CH:16]=[CH:15][N:14]=1
Reactant: O=P(Br)(Br)Br
Reactant: [O-][n+]1ccc2nn(-c3c(F)cccc3Cl)cc2c1
Solvent: ClCCl
Solvent: ClCCCl
Product: Fc1cccc(Cl)c1-n1cc2c(Br)nccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
To a suspension of 2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine 5-oxide (740 mg, 2.8 mmol) in DCE (18 mL) at 0° C. was added phosphorus oxybromide (2.4 g, 8.4 mmol). The reaction mixture was stirred at 0° C. for 15 minutes, warmed to room temperature, and stirred for an additional 4.5 h. The resultant mixture was diluted with DCM, washed with sodium carbonate (sat. aq.) and then with brine. The organic phase was dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in cyclohexane) to afford the title compound as a white solid (230 mg, 25% yield). LCMS (Method C): RT=3.44 min, m/z: 327 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][C:17]=2[CH3:32])=[CH:8][C:7]=1[CH3:33]>O>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)=[CH:18][C:17]=2[CH3:32])=[CH:8][C:7]([CH3:33])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:34])=[O:2]
Reactant: COC(=O)COc1cc(OC)c(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Solvent: O
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 39C. IR cm−1:1740, 1322; 400 MHz 1H NMR (DMSO-d6) δ 7.81 (d, 2H, J=8.1 Hz), 7.73 (d, 2H, J=8.1 Hz), 7.51 (s, 1H), 7.39 (d, 1H, J=7.8 Hz), 7.16 (d, 1H, J=7.8 Hz), 7.04 (s, 1H), 6.53 (s, 1H), 4.71 (s, 2H), 4.00 (s, 2H), 3.73 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H); MS m/z 477 (M+1). Anal. Calc'd for C25H23F3O4S.0.1 H2O; C, 62.78; H, 4.89. found: C, 62.57; H, 4.82.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[Cl:67])[CH2:56][CH2:55]1>CN(C=O)C.O>[Cl:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[NH:60][CH:57]1[CH2:58][CH2:59][N:54]([C:18](=[O:20])[CH2:17][NH:16][C:14]([C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:13][N:12]=2)=[O:15])[CH2:55][CH2:56]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1ccc(Nc2ccccc2)cn1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of [(5-phenylamino-pyridine-2-carbonyl)-amino]-acetic acid (0.035 g, 0.00013 mol) in DMF (1 mL) was added DIPEA (0.05 g, 0.00039 mol), HOBt (0.0209 g, 0.00015 mol) and EDCI.HCl (0.0296 g, 0.00015 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-chloro-phenyl)-amine dihydrochloride (0.0382 g, 0.00015 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 0.038 g (64%) of 5-phenylamino-pyridine-2-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 464.18 (M+1)+, 92.88%, 1H NMR (DMSO-d6): δ 8.9 (s, 1H), 8.5 (t, 1H), 8.3 (d, 1H), 7.9 (d, 1H), 7.55 (dd, 1H), 7.35 (t, 2H), 7.2 (m, 4H), 7.0 (t, 1H), 6.9 (d, 1H), 6.6 (t, 1H), 4.9 (d, 1H), 4.35 (d, 1H), 4.2 (d, 2H), 3.85 (d, 1H), 3.55 (s, 1H), 3.2 (m, 2H), 2.85 (m, 1H), 1.95 (t, 2H), 1.5 (m, 1H), 1.35 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:20]1[CH2:22][CH2:21]1)[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.[N+:31]([CH3:34])([O-:33])=[O:32]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:20]1[CH2:22][CH2:21]1)[CH:13]([CH2:34][N+:31]([O-:33])=[O:32])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C[C@@H](NC(=O)OCc1ccccc1)C1CC1
Agent: CN(C)C(=N)N(C)C
Product: CCOC(=O)CC(C[N+](=O)[O-])[C@@H](NC(=O)OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.1 %

Procedure:
Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-2-butenoate was dissolved in dry nitromethane (15 ml), and the solution was mixed with 1,1,3,3-tetramethylguanidine (133 μl, 1.05 mol) and stirred at room temperature for 17 hours. The reaction solution was concentrated under a reduced pressure, the resulting residue was dissolved in chloroform (50 ml), and the solution was washed with 10% citric acid aqueous solution (50 ml) and saturated sodium chloride aqueous solution (50 ml) in that order, and then dried over anhydrous magnesium sulfate, thereby obtaining 1.207 g (96.1%) of the title compound as a yellow oil. This product (diastereomer mixture) was used in the subsequent reaction without purification.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C[Si]([C:28]#[C:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([NH2:39])=[O:38])(C)C.C(O)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([NH2:39])=[O:38])#[CH:28]
Reactant: C[Si](C)(C)C#Cc1ccccc1CC(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#Cc1ccccc1CC(N)=O
Yield: 35.8 %

Procedure:
A 1.0 M solution of TBAF in THF (59.1 mL, 59.1 mmol) was slowly added to a cooled (5° C. water/ice bath) solution of 2-(2-((trimethylsilyl)ethynyl)phenyl)acetamide (I7) (11.4 g, 49.3 mmol) in DCM (150 mL) and acetic acid (3.66 mL, 64.1 mmol). The mixture was stirred at 5° C. for 1 hour before 10% aqueous NaHCO3 solution (150 mL) was added. The resulting mixture was extracted with DCM (3×50 mL) then the combined organics were dried (MgSO4), filtered and evaporated in vacuo until approximately 15 mL of solvent remained. This solution was diluted with Et2O (100 mL) and EtOAc (100 mL) resulting in the formation of a precipitate, which was filtered and dried to give 2.81 g of the title compound I8 as a brown solid. The remaining filtrate was adsorbed onto silica gel and purified using column chromatography (CombiFlash Rf, 80 g SiO2 Cartridge, 0-10% MeOH in DCM). An additional 2.62 g of the title compound I8 was isolated as a brown solid (combined total 5.43 g, 69%); 1H NMR (300 MHz, d6-DMSO) δ 7.44 (d, J=7.5 Hz, 1H), 7.21-7.37 (m, 4H), 6.93 (brs, 1H), 4.32 (s, 1H), 3.59 (s, 2H). LCMS-B: rt 4.734 min; m/z 160 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[CH3:32])[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1CN1CCC(N(C)C(=O)COc2nc(C)c(NC(=O)OC(C)(C)C)c(C)n2)CC1

Procedure:
The title compound was synthesized from Compound 31 and 2-methylbenzyl bromide in the same manner as in Example 32.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:46][C@H:47]([OH:48])[CH3:49])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@@H](C)O)CC5)cc4)cnc32)cc1
Yield: 64.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (step 1 example 103) (150 mg. 0.606 mmol) was alkylated using (R)-2-methyloxirane (22 mg, 0.371 mmol), DIPEA (96 mg, 0.74 mmol) and ethanol (3 mL) to get 160 mg (97.5% yield) of the titled compound. MS: m/z=665.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.N(CC[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)N>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NNCCN1CCOCC1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCN1CCOCC1
Reaction time: 16 h

Procedure:
Compound 28 was synthesised following similar procedures outlined in Example 31 (Compound 18), using 4-(2-hydrazinylethyl)morpholine instead of ethyl hydrazine in Step 3. As a slightly modified procedure, Step 3 was performed at 60° C. for 16 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by column chromatography (silica gel, gradient 50 to 100% ethyl acetate/isohexane), followed by preparative HPLC, yielding Compound 28 as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1>[CH:8]1([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:10][CH2:9]1
Reactant: O=C(NCCCl)NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
A 0° C. solution of 1-(2-chloroethyl)-3-cyclopropylurea (1.31 g, 8.06 mmol) in THF (40 mL) was treated with NaH (60% in mineral oil, 0.387 g, 9.67 mmol), stirred for 10 minutes, then warmed to RT and stirred for 6 h. The mixture was treated with satd. NH4Cl, the solids removed via filtration and washed with EtOAc. The filtrate was washed with brine, dried over Na2SO4 and concentrated to dryness to afford crude 1-cyclopropylimidazolidin-2-one (760 mg, 75%) which was used without further purification.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1>O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:4][CH2:3][CH2:2][OH:5])=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: OCCO
Agent: [Na]
Solvent: O
Product: COc1ccc2c(OCCO)ccnc2c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
In a 1 L RBF under nitrogen was placed sodium (15 g, 652 mmol) cubes. The flask was cooled in an ice bath and ethane-1,2-diol (150 ml, 2690 mmol) was added slowly through an addition funnel (15 min). The cooling bath was removed and the reaction mixture was allowed to warm to 50° C. until all the sodium disappeared. After 20 min, the mixture was heated to 110° C. and 4-chloro-7-methoxyquinoline (69 g, 356 mmol) was added. After 12 h, the mixture was cooled to room temperature and was diluted with H2O (250 mL), resulting the formation of a thick sludge. The content was filtered, and washed with H2O (2×50 mL). After air drying overnight, the solid was heated with benzene (300 mL) under reflux for 3 hr. The mixture was cooled and filtered. The solid was washed with ether (2×50 mL) to give a soft solid (77 g) contaminated with the small amount of bisether dimer. MS (ESI pos. ion) calcd for C12H13NO3: 219.2; found: 220.1 (MH+). 1H NMR (400 MHz, Chloroform-d) δ ppm 3.94 (s, 3H) 4.13 (t, 2H) 4.32 (t, 2H) 6.64 (d, J=5.28 Hz, 1H) 7.14 (dd, J=9.19, 2.54 Hz, 1H) 7.37 (d, J=2.35 Hz, 1H) 8.08 (d, J=9.19 Hz, 1H) 8.66 (d, J=5.48 Hz, 1H)
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:34](=[O:35])[CH2:33][CH2:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)CCc2ccc(Cl)cc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. β-(4-Chlorophenyl)propionyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[β-(4-chlorophenyl)propionyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[N:8]2)=[CH:4][CH:3]=1>O1CCCC1.NN.[Ni]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: Cc1ccc(Cn2ccc(N)n2)cc1
Reaction time: 0.08 h

Procedure:
To a solution containing 1-(4-methyl-benzyl)-3-nitro-1H-pyrazole (92 mg, 0.42 mmol) in tetrahydrofuran (2 mL), anhydrous hydrazine (100 μL) was added to the clear solution. Raney nickel (˜100 mg washed 3 times with 5 mL of anhydrous tetrahydrofuran) was then added in tetrahydrofuran (300 μL). Gas evolved from the mixture and the reaction was allowed to proceed for 5 min, after which time the raney nickel was removed by filtration through a celite plug. The solvent was removed in vacuo to afford 1-(4-methyl-benzyl)-1H-pyrazol-3-ylamine as a yellow oil which was used in the following step with no further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26](CC3C=CC(OC)=CC=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[C:22]([CH3:24])[N:23]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[C:22]([CH3:24])[N:23]=4)[C:8]=3[CH:25]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4nc(C)c[nH]4)c3cc2C2CC2)S(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c[nH]c(-c2c(-c3ccc(F)cc3)oc3cc(NS(C)(=O)=O)c(C4CC4)cc23)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1O using the compound prepared in Example 2B, (0.64 g, 1.17 mmol) and 20% trifluoroacetic acid in CH2Cl2. The title compound was isolated as a yellow solid (0.18 g, 35%). MS (ESI+) m/z 426 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2C(=C([N+]([O-])=[O:13])C=C[CH:10]=2)[CH:5]=[C:4](OC)[C:3]=1OC.C(C1C=CC(B(O)O)=CC=1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[O:38]1[CH2:43][CH2:42]O[CH2:40][CH2:39]1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:40][CH2:39][O:38][C:43]([CH3:42])=[O:13].[CH3:10][CH2:11][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1COCCO1
Reactant: COc1cc2c([N+](=O)[O-])cccc2c(Br)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCC
Temperature: 100 °C

Procedure:
1-Bromo-2,3-dimethoxy-5-nitronaphthalene (1 g), 4-t-butylphenylboronic acid (685 mg, 1.2 eq.), Pd(PPh3)4 (370 mg, 0.1 eq.), and Na2CO3 (680 mg, 2 eq.) were combined in a flask with 20 mL dioxane and 5 mL H2O and degassed. Reaction mixture was then refluxed at 100° C. overnight. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO3. The organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 20% EtOAc/hexane yielding product as a yellow solid (1.159 g, 99% yield). 1H NMR (400 MHz) (CDCl3) δ 8.18 (dd, J=8 Hz, J=4 Hz, 1H), 8.08 (s, 1H), 7.79-7.77 (m, 1H), 7.54 (dt, J=8 Hz, J=4 Hz, 2H), 7.30 (t, J=4 Hz, 1H), 7.28-7.27 (m, 2H), 3.99 (s, 3H), 3.58 (s, 3H), 1.34 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 155.05, 150.69, 147.53, 145.44, 132.89, 132.72, 131.97, 130.66, 130.06, 125.26, 123.59, 123.54 121.87, 102.16, 61.08, 55.91, 34.71, 31.43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH3:27])[C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:28]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH3:27])[C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:4][CH:3]=1
Reactant: Cc1cc(OCCCCSc2ccc(Cl)cc2)cc2c1NC(=O)OC2(C)C
Reactant: OO
Product: Cc1cc(OCCCCS(=O)c2ccc(Cl)cc2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-chloro-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH:10]=1.[CH:29](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N:8]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:29]1
Reactant: NC(=O)Cc1cnc(Nc2ccccc2N)cc1NCc1cc(F)cc(F)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: NC(=O)Cc1cnc(-n2cnc3ccccc32)cc1NCc1cc(F)cc(F)c1
Reaction time: 4 h
Yield: 94 %

Procedure:
9 mg of 6-[(2-aminophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of step 1 of Example 365) was suspended in 0.2 ml of methanol, to which 0.2 mL of trimethyl orthoformate and a catalytic amount of p-toluenesulfonic acid monohydrate were added at room temperature, and stirred at the same temperature for 4 hours. The solvent was evaporated, saturated sodium bicarbonate was added to the residue, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 9 mg (yield 94%) of the title compound as a light brown solid.