Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][C:8](=[CH2:10])[CH:7]1[C:11](OCC)=[O:12])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[OH:3][CH2:4][CH:6]1[CH2:9][C:8](=[CH2:10])[CH:7]1[CH2:11][OH:12]
Reactant: C=C1CC(C(=O)OCC)C1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=C1CC(CO)C1CO
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirred solution of 40.0 g (0.188 mol) of 1,2-bis(ethoxycarbonyl) 3-methylenecyclobutane (Cripps, H. N.; Williams, J. K.; Sharkey, W. H. J. Am. Chem. Soc. 1959, 81, 2723 2728) in 1.4 L of diethyl ether at 0° C. was added 14.4 g (0.379 mol) of lithium aluminum hydride in small portions. After 2 h at 0° C., 14.4 mL of H2O, 14.4 mL of 15% aq. NaOH, and then 44.0 mL of H2O were added sequentially. The resulting white solid was removed by filtration and washed thoroughly with diethyl ether. Concentration of the combined filtrates under reduced pressure afforded 17.1 g (71%) of the title compound as an oil, judged to be 95% pure by NMR: Rf 0.27 (silica gel, 1:1/acetone:hexane); IR (CDCl3) cm-1; 1H NMR (CDCl3) 1.66 (bs, 1H, OH), 2.24-2.41 (m, 2H), 2.44 (bs, 1H, OH), 2.57 2.71 (m, 1H), 2.87 2.96 (m, 1 H), 3.54, 3.58 (2 dd, 2H, J=J'=12 Hz, CH2O), 3.79, 3.84 (2 dd, 2H, J=10.5 Hz, J'=4.5 Hz, CH2O), 4.78, 4.82 (2 ddd, 2H, J=J'=J"=2.5 Hz, C=CH2); 13C NMR (CDCl3, CDCl3 =77.00 ppm)146.21, 105.39, 66.13, 63.74, 51.70, 38.67, 31.86; DCI-NH3MS, m/z 129 (M+1)+, 146 (M+NH4+)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:34]([O:36][C:37](=[O:63])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[C:50]([C:51](=[O:62])[NH:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([CH2:60][NH2:61])=[CH:56][CH:55]=3)=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:39]=1)[CH3:35].CN1CCOCC1>CN(C)C=O>[CH2:34]([O:36][C:37](=[O:63])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[C:50]([C:51](=[O:62])[NH:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([CH2:60][NH:61][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=4)=[CH:58][CH:59]=3)=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:39]=1)[CH3:35]
Reactant: CCOC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(CN)cc2)c1
Reactant: O=C(O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(CNC(=O)c3cccc(O)c3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
3-Hydroxy-benzoic acid (27 mg, 0.19 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol) were added to a solution of 3-[3-(4-aminomethyl-benzylcarbamoyl)-pyridin-2-yloxy]-benzoic acid ethyl ester hydrochloride (100 mg, 0.19 mmol) (see Preparation 9) and N-methyl morpholine (0.11 ml, 0.97 mmol) in N,N-dimethylformamide (15 ml). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours, concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was then purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:1, by volume) giving 3-(3-{4-[(3-hydroxy-benzoylamino)-methyl]-benzylcarbamoyl}-pyridin-2-yloxy)-benzoic acid ethyl ester (45 mg) as an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(CC)CC.[Br:34][CH2:35][C:36](Br)=[O:37]>C1COCC1>[Br:34][CH2:35][C:36]([N:6]([CH2:7][C:8]1([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12]1)[CH2:5][C:4]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:3]=1[O:2][CH3:1])=[O:37]
Reactant: COc1ccc(CNCC2(NC(=O)OC(C)(C)C)CCCC2)c(OC)c1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN(CC2(NC(=O)OC(C)(C)C)CCCC2)C(=O)CBr)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 1-{[(2,4-dimethoxybenzyl)amino]methyl}cyclopentyl-carbamate (3.20 g, 8.78 mmol) in anhydrous THF (25 mL) was added Et3N (1.35 mL, 9.65 mmol). The solution was cooled to 0° C., treated with bromoacetyl bromide (0.84 mL, 9.65 mmol), and stirred for 3 h. The reaction was poured into ice water and extracted three times into Et2O. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was subjected to column chromatography eluting with a gradient of 0-100% EtOAc/hexanes. Collection and concentration of the appropriate fractions afforded the product.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:31][C:32]([F:47])([F:46])[C:33]1[N:34]=[CH:35][C:36]([NH:39][C@H:40]2[CH2:44][CH2:43][CH2:42][C@@H:41]2[NH2:45])=[N:37][CH:38]=1.[F:48][C:49]1[C:50]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)=[C:51]([C:55]([F:58])=[CH:56][CH:57]=1)[C:52](O)=[O:53]>>[F:48][C:49]1[C:50]([N:59]2[N:63]=[CH:62][CH:61]=[N:60]2)=[C:51]([C:55]([F:58])=[CH:56][CH:57]=1)[C:52]([NH:45][C@H:41]1[CH2:42][CH2:43][CH2:44][C@@H:40]1[NH:39][C:36]1[CH:35]=[N:34][C:33]([C:32]([F:31])([F:46])[F:47])=[CH:38][N:37]=1)=[O:53]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1c(F)ccc(F)c1-n1nccn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1C(F)(F)F
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(F)ccc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(trifluoromethyl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 62) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 60 mg, 0.21 mmol) and 3,6-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 17; 50 mg, 0.21 mmol) except this was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:25]([O:27]C)=[O:26])[NH:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:13])=[CH:8][C:7]=1[Cl:23].[NH2:29][N:30]=[CH:31]S(O)(=O)=O.O.[OH-].[Li+]>CO.C(N(CC)CC)C>[Cl:23][C:7]1[CH:8]=[C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:13])[CH:10]=[CH:11][C:6]=1[C:5]([NH:4][C@H:3]([C:25]([OH:27])=[O:26])[CH2:2][NH:1][CH:31]=[N:30][NH2:29])=[O:24]
Reactant: COC(=O)[C@H](CN)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Reactant: NN=CS(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: NN=CNC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
To a solution of 3-amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (Example 72; 50 mg, 0.123 mmol) in methanol (2 mL) were added triethylamine (3 drops) and aminoiminomethanesulfonic acid (prepared according to Kim, K. et al. Tetrahedron Lett. 1988, 29, 3183-3186; 37 mg, 0.30 mmol). The reaction was stirred at room temperature overnight, and then the solvent was evaporated. The residue was suspended in tetrahydrofuran/methanol/water (3:1:1; 2 mL) and lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated and the residue was purified by reverse phase HPLC to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(aminoiminomethyl)amino-L-alanine (17 mg, 33%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCN(C(C)C)C(C)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(C(F)(F)F)cc1Br

Procedure:
A solution of 2.650 g (11.000 mmol) 2-bromo-4-trifluoromethyl-phenol and 1.47 mL 13.20 mmol) ethyl bromo-acetate in 20 mL Hünig base was stirred for 5 h at 120° C. The reaction mixture was diluted with EtOAc and the org. phase was washed with water, saturated aqueous sodium bicarbonate and saturated aqueous NaCl, dried over magnesium sulphate and evaporated down i. vac. Column chromatography (silica gel, gradient dichloromethane/MeOH 100:0→19:1) yielded the product.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[K+].CO.C(O)C>O>[CH2:1]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 90.3 %

Procedure:
A mixture of 120 g of methyl p-(tetradecyloxy)benzoate, 57.96 g of potassium hydroxide, 1-liter of methyl alcohol, 400 ml of ethyl alcohol and 60 ml of water is refluxed for 4.5 hours. A solid is formed and the reaction mixture partitioned between dilute hydrochloric acid and chloroform with some warming. The organic layer is washed with warm dilute hydrochloric acid and dried. The filtrate is evaporated to a volume of 600 ml and an equal volume of hexanes added to form a solid which is dried to give 104 g of the desired product as a white solid, m.p. 94°-96° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][C:5]([CH2:6]N(C)C)=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17].[P:20]([O:25]C)([O:23][CH3:24])[O:21][CH3:22].C(OC(=O)C)(=O)C>>[OH:1][C:2]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][C:5]([CH2:6][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: COP(OC)OC
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: COP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A thermostatically controllable reactor is charged with 263 g (1 mol) of (4-hydroxy-3,5-di-tert-butylbenzyl)dimethylamine und 500 g of petroleum ether 100/140. With stirring and blanketing with inert gas, the reaction mixture is heated to 80° C. and 130 g (1.05 mol) of trimethyl phosphite are run into the clear solution. With cooling, 107 g (1.05 mol) of acetic anhydride are then added dropwise over 2 hours at 80° C., and stirring is continued for 2 hours at 80° C. The solvent is removed by distillation until the temperature is 115° C. The residual reaction solution is cooled to room temperature and stirred with 1 liter of water. The crystallised product is filtered with suction, washed with petroleum ether 100/140 and dried, giving 307 g (93% of theory) of almost colourless dimethyl 4-hydroxy-3,5-di-tert-butylbenzylphosphonate of m.p. 156°-160° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][O:7][C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:12][N:11]=[C:10]([NH:26][C@H:27]3[CH2:32][CH2:31][C@@H:30]([CH3:33])[CH2:29][CH2:28]3)[N:9]=2)[CH2:2]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:34][S:35]([N:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][O:7][C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:18][CH:19]=3)=[CH:12][N:11]=[C:10]([NH:26][C@H:27]3[CH2:28][CH2:29][C@@H:30]([CH3:33])[CH2:31][CH2:32]3)[N:9]=2)[CH2:2]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OC[C@@H]3CCNC3)n2)CC1
Product: CS(=O)(=O)N1CC[C@@H](COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 5, 4-(((R)-pyrrolidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine with methanesulfonyl chloride to provide the title compound in 67% yield. 1H NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.33 (d, 2H), 6.94 (d, 2H), 5.40 (sb, 1H), 4.35 (m, 2H), 4.08 (m, 1H), 3.88 (m, 4H), 3.55-3.31 (m, 4H), 3.18 (m, 4H), 2.76 (s, 3H), 2.17-2.10 (m, 1H), 1.86-1.25 (m, 9H), 0.95 (d, 3H); MS (ESI) m/z: Found: 530.3 (M+1). Calc. 529.3 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)C1CCCCC1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)cyclohexanecarboxamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and cyclohexane carbonyl chloride to give a tan solid (62% yield). 1H-NMR (CDCl3): δ 8.86 (s, 1H), 7.58 (m, 1H), 7.21 (dd, 1H), 7.16 (d, 1H), 5.74 (m, 1H), 5.07 (m, 1H), 2.66 (m, 2H), 2.26-2.05 (m, 2H), 1.96-1.72 (m, 7H), 1.70-1.63 (m, 1H), 1.52-1.35 (m, 2H), 1.31-1.16 (m, 3H); MS m/z 375 (M−1):
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C1COCC1.O>CO.[Fe]>[NH2:19][C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Yield: 100 %

Procedure:
A solution of the product of Example 38a (2.7 g, 8.97 mmol), iron powder (2.0 g, 35.9 mmol) and ammonium chloride (0.58 g, 10.76 mmol) in a methanol (6 mL), THF (6 mL), and water (2 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (2.46 g, 77%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH2:14][CH3:15])[N:5]=[C:4]([NH:16][CH3:17])[N:3]=1.[C:18]([C:20]1[C:25]([F:26])=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:30])#[N:19].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH2:14]([C@@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[N:5]=[C:4]([NH:16][CH3:17])[N:3]=[C:2]([C:23]2[CH:24]=[C:25]([F:26])[C:20]([C:18]#[N:19])=[C:21]([F:30])[CH:22]=2)[CH:7]=1)[CH3:15]
Reactant: CC[C@@H]1COCCN1c1cc(Cl)nc(NC)n1
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(NC)n1
Temperature: 140 °C
Yield: 129.4 %

Procedure:
4-Chloro-6-[(3R)-3-ethyl-4-morpholinyl]-N-methyl-2-pyrimidinamine (250 mg, 0.974 mmol) was added to a 20 mL microwave vial, followed by (4-cyano-3,5-difluorophenyl)boronic acid (356 mg, 1.948 mmol), PdCl2(dppf).CH2Cl2 adduct (39.8 mg, 0.049 mmol), 2M K2CO3 (1.461 mL, 2.92 mmol) and 1,4-dioxane (4 mL). The mixture was heated to 140° C. for 10 minutes. The reaction mixture was filtered through a silica plug and washed with EtOAc (3×). The filtrate was then washed with H2O (2×) and the organic layer was dried over Na2SO4 and concentrated to afford the title compound (453 mg) as a brown oil. LC-MS (ES) m/z=360 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1/[N:13]=[CH:14]/[C:15]1[N:20]=[C:19]([C:21]2[CH:41]=[CH:40][CH:39]=[CH:38][C:22]=2[CH2:23][N:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C(=O)OC(C)(C)C)[CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[BH3-]C#N.[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>C(O)=O.CO>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([C:21]2[CH:41]=[CH:40][CH:39]=[CH:38][C:22]=2[CH2:23][NH:24][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:20]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(-c2ccccc2CN(C(=O)OC(C)(C)C)c2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O=CO
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(-c2ccccc2CNc2ccccc2)n1
Temperature: 25 °C

Procedure:
Methanol (40 mL) and (E)-tert-butyl 2-(6-((2,6-diisopropylphenylimino)methyl)pyridin-2-yl)benzyl(phenyl)carbamate (12) (2.56 g (4.67 mmol) were combined to form a yellow suspension. Then some NaBH3CN (0.293 g, 4.66 mmol) was added followed by four drops of 88% formic acid. Then additional NaBH3CN (0.878 g, 14.0 mmol) was added in small portions over 5 minutes. The mixture was heated to reflux for 3 hours then evaporated to near dryness. Water (20 mL) and Et2O (40 mL) were then added followed by a CH2Cl2 (6 mL). The organics were separated, dried over brine then magnesium sulfate, filtered, and evaporated to a thick oil. Chloroform (25 mL) was then added to form a solution. Trifluoroacetic acid (10 mL) was added and the mixture was heated to reflux to cause gas evolution. After 45 minutes the mixture was cooled to ambient temperature and 3 M NaOH (60 mL) was added. The biphasic mixture was rapidly stirred for several minutes. The organics were separated, washed with water (50 mL) and brine (5 mL). The organics were then separated and dried over magnesium sulfate. Filtration and evaporation afforded the product as a thick oil that was dried thoroughly under reduced pressure at 65° C. Yield: 2.0 g, 95%). 1H NMR (CD2Cl2, 500 MHz): 7.77 (t, 1H), 7.39-7.58 (m, 5H), 7.31 (d, 1H), 7.02-7.12 (m, 5H), 6.63 (t, 1H), 6.58 (d, 2H), 4.62 (br, 1H), 4.41 (br, 2H), 4.23 (br, 1H), 3.97 (br, 1H), 3.35 (sept, 2H), 1.20 (d, 12H).
Reaction SMILES: [NH:1]1CCCN1C(O)=O.CC#N.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([NH:18][C:19]([NH2:1])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)N1CCCN1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 247.9 %

Procedure:
To a solution of azaproline VI (20.0 mg, 0.056 mmol) and TEA (9.5 pt, 0.068 mmol) in DCM (400 μL)/MeCN (750 μL) was added phenylisocyanate (7.3 μL, 0.067 mmol). The solution was stirred at rt for 16 h then concentrated in vacuo. The crude residue was purified by silica gel chromatography (ethyl acetate-hexanes) to afford 18.9 mg of phenylurea in 71% yield. LCMS (M+1): 474.84.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[O:8][CH2:9][CH3:10].B(OCCCC)(OCCCC)OCCCC.I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>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.CCCCCC.C1COCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:4][C:3]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1sc(Br)cc1Br
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCOB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOc1sc(-c2ccccc2)cc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
150 ml of anhydrous THF and 6.5 g (23 mmol) of 3,5-dibromo-2-ethoxythiophene was added into a flask under argon atmosphere. Then, 15 ml (25 mmol) of a solution containing 15% n-butylithium hexane was slowly dripped into it at −78° C. After being stirred for 1 hour at −78° C., 9.1 ml (34 mmol) of tri-n-butyl borate was slowly dripped into it and was stirred for 1.5 hours. After being returned to a room temperature and quenched with water, 4.6 g (23 mmol) of iodobenzene, 1.1 g (0.95 mmol) of Pd(PPh3)4, and 50 ml of 20 wt % Na2CO3 aqueous solution was added to the solution and was refluxed overnight at 70° C. The reaction solution was extracted with ether, was washed with a salt solution, and was dried with magnesium sulfate. After filtering out the magnesium sulfate and evaporating the solvent, the product was developed with hexane on a silica column to give 3-bromo-2-ethoxy-5-phenylthiophene (Rf=0.31). The yield was 4.9 g in weight and 76% in percentage.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)[CH3:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([CH2:48][OH:49])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>ClCCl.C1CCCCC1>[Cl:24][C:9]1[CH:8]=[C:7]([CH:5]([O:49][CH2:48][C:35]2([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.1 g, 2.33 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.79 g, 2.57 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 10 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (64 μL, 0.47 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate, and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.81 g (56%) as a clear film. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.30-7.33 (m, 2H), 7.01-7.05 (m, 2H), 6.77 (m, 1H), 5.62-5.68 (s, 2H), 4.93 (q, J=6.4 Hz, 1H), 3.72 (m, 2H), 3.58-3.61 (m, 2H), 3.33-3.39 (m, 2H), 3.03-3.08 (m, 2H), 2.08-2.22 (m, 2H), 1.87-1.97 (m, 2H), 1.44 (s, 9H), 1.43 (d, J=6.4 Hz, 3H), 0.91-0.92 (m, 2H), 0.05 (s, 9H). Mass spec.: 618.86 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O-])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Na+].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.C(O)(=O)C.CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=C([O-])c1ccc(-c2ccncc2)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccncc2)cc1
Reaction time: 0.25 h
Yield: 33.4 %

Procedure:
A solution of sodium 4-(4-pyridyl)benzoate (500 mg, 2.26 mmol), and N-methylmorpholine (0.250 mL, 2.26 mmol) in tetrahydrofuran (12 mL) was treated with ethyl chloroformate (0.216 mL, 2.26 mmol). After 0.25 h, the mixture was treated with sodium borohydride (256 mg, 6.79 mmol) followed by methanol (24 mL) dropwise. After 0.5 h, the mixture was treated with 10% aqueous acetic acid and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide. The aqueous layer was extracted twice with ethyl acetate and the combined extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo to yield 140 mg of the title compound which was used without further purification.