Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]1[CH2:44][O:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>CO>[N:48]1[CH:49]=[CH:50][CH:51]=[C:46]([O:45][CH2:44][CH:32]2[CH2:33][NH:34][CH2:35][CH2:36][N:31]2[C:23]2[S:22][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)[CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(OCC2CNCCN2c2nc3ccccc3s2)c1
Reaction time: 12 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (116.4 mg, 0.215 mmol) in MeOH (1 mL). After 12 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 41.7 mg (59%) of the desired product as an off-white, sticky solid. LC-MS: RT=4.38 min, [M+H]+=327.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1)([O-:3])=[O:2].[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc([N+](=O)[O-])ccn1
Solvent: c1ccncc1
Product: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
4-nitropyridin-2-amine (Int-22, 32.4 g, 0.2096 mol) was dissolved in pyridine (200 mL). The reaction was cooled in an ice-water bath and cyclopropanecarbonyl chloride (28.5 mL, 0.314 mol) was added dropwise. Upon completing addition of the acid chloride, the reaction was stirred for 1 hr at 0° C. then warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and then diluted with water. Solids were collected by suction filtration. The filter cake was washed with water and hexanes. The isolated solids were then dried under vacuum to afford N-(4-nitropyridin-2-yl)cyclopropanecarboxamide (43.5 g, 100%). LCMS: (FA) ES+ 208; 1H NMR (300 MHz, CDCl3) δ ppm 8.90 (s, 1H), 8.50 (s, 1H), 8.50 (br s, 1H), 7.7 (dd, 1H), 1.6 (m, 1H), 1.2 (m, 2H), and 1.0 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C:23]1([CH3:40])[CH2:26][N:25]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1)=[N+]=[N-]>C1COCC1.O>[CH:27]([N:25]1[CH2:26][C:23]([NH2:20])([CH3:40])[CH2:24]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(N=[N+]=[N-])CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(N)CN(C(c2ccccc2)c2ccccc2)C1
Yield: 84.1 %

Procedure:
A solution of triphenylphosphine (3.97 g, 15.14 mmol) and 3-azido-1-benzhydryl-3-methyl-azetidine (2.1 g, 7.57 mmol) in THF (20 mL) and water (2 mL) was stirred for 48 h. The solvent was removed in vacuo and a solution of hydrochloric acid (1M, 100 mL) was added to the residue. The aqueous solution was washed with DCM (50 mL) and the aqueous solution was basified to pH 8 with a solution of sodium hydroxide in water (1M). Then, the aqueous solution was extracted with EtOAc (3×50 mL). The combined organic phase was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10-100% EtOAc in petroleum ether) to give crude 1-benzhydryl-3-methyl-azetidin-3-ylamine (1.6 g, 6.37 mmol, 84%). 1H NMR (CDCl3, 400 MHz): δ7.40-7.33 (m, 4H), 7.21-7.25 (m, 4H), 7.12-7.18 (m, 2H), 4.22-4.30 (m, 1H), 3.10-3.20 (m, 2H), 2.80-2.92 (m, 2H), 1.41-1.47 (m, 3H). The two NH2 protons were not observed in CDCl3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[CH:38]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1>[CH:38]1([C:42]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)=[O:43])[CH2:41][CH2:40][CH2:39]1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CCC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol) in tetrahydrofuran (5 mL) were added dropwise triethylamine (75 μL, 0.544 mmol) and cyclobutanecarbonyl chloride (50 μL, 0.435 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (98 mg, 54%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])CCC.CN([CH:18]=[O:19])C.[Na+].[Cl-]>C(OCC)C>[CH:18]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)=[O:19]
Reactant: COc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COc1cncc(C=O)c1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-Bromo-5-methoxypyridine (2.5 g, 13.3 mmol) in anhydrous diethyl ether cooled to −100° C. was added n-butyllithium (2.5M soln in hexanes: 5.85 mL, 14.6 mmol) dropwise whilst maintaining an internal temperature <−94° C. After subsequent stirring for 30 minutes, anhydrous DMF (1.34 mL, 17.3 mmol) was added and the reaction mixture allowed to warm to −60° C. The solution was then poured into sat'd. aq. NaCl soln. and extracted with diethyl ether (3×100 mL), the ethereal phase dried (K2CO3), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 30% EtOAc in hexanes to afford the title material as an oil.
Reaction SMILES: NCC1C=CC(NC2SC3CCCC4C=CC(F)=CC=4C=3N=2)=CC=1.[NH2:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=1.[C:41]([N:49]=[C:50]=[S:51])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:41]([NH:49][C:50]([NH:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:28][CH:27]=1)=[S:51])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: NCc1ccc(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=S)NC(=O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a stirred solution of N2-[4-(aminomethyl)phenyl]-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-amine-tert-butyl N-(4-aminobenzyl)carbamate (6.00 g, 27.0 mmol) in anhydrous THF (50 ml) was added benzoylisothiocyanate (4.43 g, 27.0 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo to yield 100% (10.4 g) of the protected thiourea as a yellow solid: m.p. 161-163° C. 1H-NMR (CDCl3) δ 1.45 (9H, s), 4.33 (2H, d), 4.85 (1H, broad), 7.34 (2H, d), 7.60 (5H, m), 7.90 (2H, d), 9.13 (1H, s), 12.58 (1H, s); 386 (ESMS, MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20].[I-:27].[Na+].CC(=O)CC>CCOCC>[I:27][CH2:2][CH2:3][C@H:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20]
Reactant: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCI)c1ccccc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A dry 1-L R.B. flask was charged (R)-3-chloro-1-phenyl-1-(2-methyl-4-((tert-butoxycarbonyl)oxy)phenoxy)propane (18.00 g, 47.80 mmol), sodium iodide (90.0 g, 600 mmol) and 2-butanone (550 mL). The reaction flask was protected from light. The reaction mixture was stirred at reflux temperature under nitrogen for 16 hours. The mixture was cooled to room temperature and poured into ether (1 L). The insoluble inorganic salts (white precipitate) were removed by filtration. The filtrate was concentrated under reduced pressure and the crude residue was dissolved in diethyl ether (1 L). The ethereal layer was washed with cold saturated sodium bisulfite solution (2×200 mL), water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with 20% ethyl acetate in hexane to provide 20.5 grams (91%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]([OH:29])[C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:26](=[O:27])[CH:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=3)[OH:29])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Agent: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Product: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)C(O)c3cccc(Cl)c3)ccc21

Procedure:
5-Amino-indazole-1-carboxylic acid tert-butyl ester was prepared following the procedure outlined by S. J. Brickner, WO9002744. 5-Amino-indazole-1-carboxylic acid tert-butyl ester was then coupled with 2-(3-chlorophenyl)-2-hydroxyacetic acid following the procedure as described in Example 1 to afford 5-[2-(3-chloro-phenyl)-2-hydroxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester. To a solution of 5-[2-(3-chloro-phenyl)-2-hydroxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester (7.47 mmol) in dry THF (20 mL) at 0° C. was added pyridine (37.33 mmol, 5 equivalents) followed by methanesulfonyl chloride (22.40 mmol, 3 equivalents) added in a dropwise fashion. The resultant solution was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuo and the resulting oil was partitioned between EtOAc and brine. The organic layer was washed with brine (thrice), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (3.58 g, qunatitative yield), which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[N:7]([CH3:22])[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[CH:9]=2.[OH-].[Na+]>CO>[CH3:21][O:20][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:23])=[O:2])[N:7]2[CH3:22])=[CH:12][CH:11]=1
Reactant: CCCCCc1c(/C=C/C(=O)OC)n(C)c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCc1c(/C=C/C(=O)O)n(C)c2cc(OC)ccc12
Yield: 47.6 %

Procedure:
As in Example 112, (E)-3-(6-methoxy-1-methyl-3-pentylindol-2-yl)-2-propenoic acid methyl ester (2 g) in methanol (25 mL) was treated with 4N sodium hydroxide solution (3 mL) at reflux for 2.5 hours. The crude reaction product was isolated in the usual manner giving 0.91 g of (E)-3-(6-methoxy-1-methyl-3-pentylindol-2-yl)-2-propenoic acid. A small sample was crystallized from diethyl ether to give the analytical specimen, mp 157°-158° C. Anal. Calcd for C18H23NO3 : C, 71.73; H, 7.69; N, 4.65 Found: C, 72.06; H, 7.65; N, 4.82
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].Cl.[CH3:27][O:28][C:29](=[O:59])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:35](=[O:58])[CH2:36][N:37]([C:39](=[O:57])[C@H:40]([CH2:42][CH2:43][CH2:44][CH:45]([C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[NH2:46])[NH2:41])[CH3:38].C1(N=C=NC2CCCCC2)CCCCC1.COC(=O)[C@@H]1CCCN1C(=O)CN(C(=O)[C@](C(OC(C)(C)C)=O)(CCCC(C(OCC1C=CC=CC=1)=O)N)N)C>C(Cl)(Cl)Cl>[CH3:27][O:28][C:29](=[O:59])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:35](=[O:58])[CH2:36][N:37]([C:39](=[O:57])[C@H:40]([CH2:42][CH2:43][CH2:44][CH:45]([C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[NH2:46])[NH:41][C:23](=[O:25])[CH2:22][NH:21][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])[CH3:38]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN(C)C(=O)[C@@H](N)CCCC(N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: COC(=O)[C@@H]1CCCN1C(=O)CN(C)C(=O)[C@@](N)(CCCC(N)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)CN(C)C(=O)[C@H](CCCC(N)C(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Yield: 73.4 %

Procedure:
To 50 ml of a solution of 2.79 g (0.0078 mol) of tertiary butyloxycarbonylglycine dicyclohexylamine salt and 3.96 g (0.0078 mol) of ε-benzyloxycarbonyl-L-lysyl-sarcosyl-L-proline methyl ester hydrochloride in chloroform, 5 ml of a solution of 1.61 g (0.0078 mol) of dicyclohexylcarbodiimide in chloroform was added at -10° C. Thereafter, the resultant mixture was treated by the procedure followed in the preparation of α-tertiary butyloxycarbonyl-ε-benzyloxycarbonyl-L-lysylsarcosyl-L-proline methyl ester in (A) above including such step as stirring at -10° C. for five hours and at room temperature overnight, for example. Consequently, there was obtained 3.55 g (yield 73%) of tertiary butyloxycarbonylglycyl-ε-benzyloxycarbonyl-L-lysyl-sarcosyl-L-proline methyl ester in white solid form having a melting point of 52° to 54° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][C@H:5]([C:9]([N:11]1[C@H:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=3)[N:24]=2)[CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].B([C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([NH:4][C@@H:5]([CH:6]([CH3:8])[CH3:7])[C:9]([N:11]1[C@H:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:36]4[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=4)=[CH:27][CH:26]=3)[N:24]=2)[CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12]1)=[O:10])=[O:32]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1nc(-c3ccc(Br)cc3)c[nH]1)OCCO2)C(C)C
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1nc(-c3ccc(-c4ccc(C(=O)O)cc4)cc3)c[nH]1)OCCO2)C(C)C
Yield: 67.6 %

Procedure:
To a solution of ((S)-1-{(S)-8-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-1,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (450 mg, 0.89 mmol) in dioxane (8 mL) and water (4 mL) was added 4-boronobenzoic acid (154 mg, 0.93 mmol), sodium carbonate (189 mg, 1.78 mmol), and tetrakis(triphenylphosphine)-palladium(0) (104 mg, 0.09 mmol) and the reaction mixture was stirred at reflux for 3 h under nitrogen. The pH was adjusted to 1 with 2 M HCl, and the reaction mixture was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over sodium sulfate, concentrated and purified by flash chromatography (eluted with methanol in DCM, 0 to 7%) to provide the title intermediate as a yellow solid (330 mg, 68% yield). (m/z): [M+H]+ calcd for C29H32N4O7 549.23. found 549.3. 1H NMR (CH3OD, 400) δ (ppm) 8.13-8.11 (m, 2H), 7.90-7.78 (m, 7H), 5.39-5.34 (m, 1H), 4.19-3.91 (m, 7H), 3.66 (s, 3H), 2.72-2.65 (m, 1H), 2.48-2.41 (m, 1H), 2.12-1.95 (m, 1H), 0.92-0.85 (m, 6H).
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-])=O)(C)C)(C)(C)C.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)ccc1OCCCO
Temperature: 80 °C
Yield: 87.1 %

Procedure:
To a solution of tert-butyl-[3-(4-chloro-2-nitro-phenoxy)-propoxy]-dimethyl-silane (0.37 g, 1.07 mmol), in a mixture of ethanol (10 mL) and water (3 mL), were added ammonium chloride (0.3 g, 5.37 mmol) and iron powder (0.3 g, 5.6 mmol) and the resulting mixture was heated at 80° C. overnight. The solid was filtered through a CELITE™ pad, the filter cake was washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug to give 0.188 g (87% yield) of 3-(2-amino-4-chloro-phenoxy)-propan-1-ol as a yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.CO>O1CCCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ccc(CCO)cc1
Yield: 86.4 %

Procedure:
5.5 ml 1 M borane-tetrahydrofuiran complex was slowly added to a solution of 1 g (5.5 mmole) 4-(methylmercapto)phenyl acetic acid in 5 ml tetrahydrofuran at −10° C. The reaction mixture was allowed to reach room temperature and the reaction was followed by TLC. After completion 10 ml methanol was added and the solvents were evaporated. Diethyl ether and 2 M sodium hydroxide was added, the phases were separated, the organic phase was dried, filtered and evaporated in vacuo to give 0.8 g (yield 84.4%) of 2-[4-(methylmercapto)phenyl]-1-ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCCC1.C[Si]([N-:56][Si](C)(C)C)(C)C.[Li+]>Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:56])[CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COCCOc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Product: COCCOc1ccnc(N)c1
Temperature: 60 °C
Yield: 78 %

Procedure:
A steady stream of nitrogen was passed through a mixture of 2-chloro-4-(2-methoxyethoxy)pyridine (50.17 g, 267.4 mmol), Pd2dba3 (4.897 g, 5.348 mmol), XPHOS (5.099 g, 10.70 mmol) and tetrahydrofuran (445.7 ml) for 10 minutes. To the resulting degassed mixture was added lithium bis(trimethylsilyl)amide (561.5 ml, 561.5 mmol). After addition, the resulting mixture was heated to 60° C. for 18 hours. The reaction was cooled to ambient temperature and diluted with 1 N hydrochloric acid (200 mL). The resulting solution was washed twice with 500 ml of methyl-tert-butyl ether. The pH of the aqueous layer was taken to 11 with 6 N NaOH and was extracted with dichloromethane (3×500 ml). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to yield title compound. (35 g, 78% yield) MS APCI (+) m/z 169 (M+1) detected.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[C:18]4[NH:22][C:21](=[O:23])[NH:20][C:19]4=[O:24])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>O.C(O)C.[Pd]>[O:23]=[C:21]1[NH:22][CH:18]([CH2:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:19](=[O:24])[NH:20]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C=C4NC(=O)NC4=O)cc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CN1CCC(c2c[nH]c3ccc(CC4NC(=O)NC4=O)cc23)CC1
Yield: 98.8 %

Procedure:
The product from step (c) (2.4 g) was suspended in a mixture of water (100 ml) and ethanol (200 ml) and 10% w/w Pd/C (0.25 g) added. The mixture was stirred under 1 atmos. pressure of hydrogen for 17 hours when uptake was complete. The mixture was filtered through Hyflo and the filtrate evaporated in vacuo to give the desired product as a colourless solid (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(S(C)(=O)=O)CC4)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a suspension of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (0.16 g, 0.43 mmol) in anhydrous DCM (10.0 mL) were added DMAP (0.011 g, 0.092 mmol) and Et3N (0.15 mL, 1.10 mmol), followed by methanesulfonyl chloride (0.076 g, 0.66 mmol) at 0° C. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a light yellow solid (0.14 g, 72%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C:6]1([NH:12][CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl.[CH3:15]N>>[ClH:1].[CH3:2][O:3][C:4]([C:6]1([NH:12][CH2:13][CH3:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CN
Reactant: CNC1(C(=O)OC)CCCCC1
Agent: Cl
Product: CCNC1(C(=O)OC)CCCCC1

Procedure:
1-Ethylaminocyclohexane-1-carboxylic acid methyl ester hydrochloride was prepared by the same methods as 1-methylaminocyclohexane-1-carboxylic acid methyl ester hydrochloride, substituting ethylamine hydrochloride for methylamine hydrochloride, in the first step.
Reaction SMILES: [N:1]([CH:4]([CH2:8][CH2:9][C:10]#[N:11])[C:5](O)=[O:6])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N:1]([CH:4]([CH2:8][CH2:9][C:10]#[N:11])[C:5]([Cl:15])=[O:6])=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CCCC(N=[N+]=[N-])C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCCC(N=[N+]=[N-])C(=O)Cl
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 2-azido-4-cyanobutyric acid (0.76 g, 4.94 mmol) in dry methylene chloride (20 ml) was added oxalyl chloride (0.65 g, 5.1 mmol) and a drop (~15 mg) of DMF. The reaction mixture was stirred at room temperature until the evolution of gas ceased (15 min) and then refluxed for 10 min. Removal of the solvent in vacuo gave 0.84 g (99%) of the title compound as a syrup; ir (neat) νmax : 2250, 2110, 1780 cm-1.