Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[Na+].Cl.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:18](=[O:15])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccncc1)C(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A solution of N'-t-butyl-N'-benzoylhydrazine (0.5 g, 0.00026 mol) in 10 ml of toluene was treated with 50% sodium hydroxide (0.6 g) followed by isonicotinyl chloride hydrochloride (0.47 g, 0.0026 mol). The mixture was stirred at 23° C. overnight. The solids were removed by filtration and washed with isonicotinyl-N'-benzoylhydrazine.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[CH2:7][N:6]([CH3:18])[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@@H:8]2[CH2:7][N:6]([CH3:18])[CH2:5][C@H:4]2[NH2:1])=[CH:11][C:12]=1[F:17]
Reactant: CN1C[C@@H](N=[N+]=[N-])[C@H](Oc2ccc(Cl)c(F)c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN1C[C@@H](N)[C@H](Oc2ccc(Cl)c(F)c2)C1
Yield: 19.6 %

Procedure:
To a solution of 426 (0.480 g, 1.77 mmol), PPh3 (0.930 g, 3.54 mmol) and THF (10 mL) was added H2O (1.0 mL). The resultant mixture was heated at 55° C. for 3 h. The solvent was removed in vacuo. The residue was purified by SiO2 chromatography eluting with DCM/MeOH (5:1 DCM/MeOH then 1:1) to afford 85 mg (21% over 5 steps) of trans-(±)-4-(4-chloro-3-fluorophenoxy)-1-methylpyrrolidin-3-amine (428): LC-MS (ESI) m/z 245 (M+H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([C:23](O)=[O:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[C:26]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:26]([N:30]1[CH2:35][CH2:34][N:33]([C:23]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][CH2:20][N:21]4[CH:22]=[C:9]([C:8]5[N:4]([CH:2]([CH3:3])[CH3:1])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:12]=3[CH:13]=2)=[O:24])[CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: CC(C)(C)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)N3CCN(C(C)(C)C)CC3)ccc1OCC2
Temperature: 100 °C
Yield: 36.7 %

Procedure:
To a solution of 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-13-carboxylic acid (50 mg, 0.147 mmol) in DMF (2 mL) was added 1-tert-butylpiperazine (42 mg, 0.296 mmol), DIPEA (57 mg, 0.442 mmol) and HATU (112 mg, 0.295 mmol). The reaction mixture was heated at 100° C. for 2 h. The resultant mixture was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 110 (25 mg, 37% yield) as an off-white solid. LCMS (ESI): RT=4.95 min, m/z: 464.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.38-7.36 (dd, J=2.0, 8.5 Hz, 1H), 7.12-7.11 (d, J=8.5 Hz, 1H), 5.80 (m, 1H), 4.56 (s, 4H), 3.7-3.3 (m, 4H), 2.90 (s, 1H), 2.87 (s, 1H), 1.50-1.48 (d, 6H), 1.03-1.02 (m, 11H)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](O)C=C2)=C(Cl)N=1.[CH:55]([N:58]1[CH:62]=[C:61]([CH2:63][CH2:64][NH2:65])[N:60]=[CH:59]1)([CH3:57])[CH3:56]>>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:65][CH2:64][CH2:63][C:61]3[N:60]=[CH:59][N:58]([CH:55]([CH3:57])[CH3:56])[CH:62]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)n1cnc(CCN)c1
Agent: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCc4cn(C(C)C)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared from N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (compound of Example 4) and 2-(1-isopropyl-1H-imidazol-4-yl)-ethylamine using a procedure analogous to that of Example 9 for the desired salt. MS (ES+) m/e 638 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@:24]([OH:28])([CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][C@@:24]1([CH3:27])[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
(S)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 65.1, 60 mg, 0.130 mmol), pyrimidin-5-ylboronic acid (32.3 mg, 0.261 mmol), Pd(PPh3)2Cl2 (9.15 mg, 0.013 mmol) and Na2CO3 (41.5 mg, 0.391 mmol) were added to a MW vial and treated with a mixture of DME (553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed, evacuated/purged with argon and was subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (1.44 mmol/g, 45.3 mg, 0.065 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Silica, from 23% to 28% in 6 min.) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=0.94 min, m/z=460.4 [M+H]+, m/z=458.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 3H) 1.66-1.84 (m, 2H) 2.95 (d, J=11.80 Hz, 1H) 3.02 (d, J=11.17 Hz, 1H) 3.17-3.26 (m, 1H) 3.37-3.47 (m, 1H) 4.75 (s, 1H) 7.35 (d, J=8.53 Hz, 2H) 7.85 (d, J=9.16 Hz, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.78 (d, J=2.13 Hz, 1H) 8.89 (s, 2H) 9.16-9.24 (m, 1H) 10.18 (s, 1H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]4C=C[CH:8]([CH2:9]4)[CH:7]3[CH:3]([CH2:4]2)[CH2:2]1>C1(C)C=CC=CC=1>[CH:3]12[CH2:4][CH:5]([CH2:6][CH2:7]1)[CH:1]=[CH:2]2.[CH2:8]1[CH:7]2[CH:3]3[CH:2]=[CH:1][CH:5]([CH:6]2[CH:10]=[CH:9]1)[CH2:4]3
Reactant: C1=CC2CC1C1C3CCC(C3)C21
Solvent: Cc1ccccc1
Product: C1=CC2C3C=CC(C3)C2C1
Product: C1=CC2CCC1C2

Procedure:
Tetracyclododecene (20 g) containing 35,000 ppm of the compound having a molecular weight of 188 obtained in Example 2, norbornene (2.5 g), dicyclopentadiene (2.5 g) and toluene (200 ml) were introduced into an entirely dried autoclave of 500 ml. Triethylaluminum (3 mmol) was added to the above mixture, and further, tetrachlorotitanium (0.7 mmol) and triethylamine (7 mmol) were added to carry out a ring opening polymerization at 30° C. for 6 hours.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18].CC(C)([O-])C.[K+]>CN(C=O)C>[OH:22][C:16]1[C:17](=[O:18])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6](=[O:7])(=[O:8])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCCNS(=O)(=O)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 6.1 %

Procedure:
A solution of N-(2-methoxyethyl)-1-phenylmethanesulfonamide (3.5 g, 14.5 mmol) and diethyl oxalate (2.33 g, 16.0 mmol) in dry DMF was cooled in an ice-bath. Potassium tert-butoxide (2.17 g, 18.4 mmol) was added and after 5 mins the ice-bath was removed and the reaction was stirred at rt for 22 h. 2M HCl (45 mL) was added to the mixture and the acidic solution was extracted 3 times with dichloromethane. The combined organic layers were washed 4 times with water, dried through a phase separator and evaporated. The residue was purified by preparative HPLC [0.1M NH4OAc/MeCN, (9:1 to 1:9)] to give the title compound (0.250 g, 6%) as a solid; 1H NMR (500 MHz, CD3OD): δ 7.90-7.94 (m, 2H), 7.28-7.33 (m, 2H), 7.10-7.15 (m, 1H), 3.79 (t, 2H), 3.68 (t, 2H), 3.34 (s, 3H); Mass Spectrum: M−H+ 282.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:24]([O:26][C:27](=[O:32])[CH2:28]C(O)=O)[CH3:25]>O1CCCC1>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:25]
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(O)CCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCCn1ccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
To a suspension of 4-(1-imidazolyl)butyric acid (0.5 g) in tetrahydrofuran (35 ml), 1,1'-carbonyldiimidazole (0.578 g) was added, followed by stirring at room temperature for 6 hours. After magnesium salt of malonic acid monoethyl ester [Mg(OCOCH2COOC2H5)2 ] (1.02 g) was added, the mixture was stirred at room temperature for 18 more hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1, v/v) to yield 6-(1-imidazolyl)-3-oxohexanoic acid ethyl ester (0.32 g, 44%) as an oily substance.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[N-:7]=[N+:8]=[N-:9].[Na+]>C1C=CC=CC=1.Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]=[N+:8]=[N-:9])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C=NCCCl
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(=O)NCCCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A solution of 2-chloroethyl isocyanate (0.2 mole) in 100 ml of benzene was slowly added to a stirred solution of activated sodium azide (0.2 mole) in 100 ml of hydrochloric acid (13%) maintained at 0° C. The two-phase reaction mixture was stirred for 4 hours at 0° C. and the water phase was removed. 2-chloroethylcarbamoyl azide was crystallized from benzene/petroleum ether in the form of white needles. Yield: 88%. M.P. 49.6 to 50.2° C. NMR(CDCl3 -TMS)δ=3.4 to 3.9 ppm (unres., 4H, CH2 --CH2Cl); 6.12 ppm (br, s, iH, NH); MS(14 v):m/e 148(M+), m/e 106(M--N3)+, m/e 105 (M--HN3)+=base peak. An intensity ratio of m/e 148 / m/e 150 is typical for a monochlorinated compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[C:52](=[O:53])[N:25]2[C:26]([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])=[C:27]([CH2:30][O:31][C:32](=[O:35])[NH:33][CH3:34])[CH2:28][S:29][C@H:24]12.CN1CCOCC1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH:19]([CH3:21])[CH3:20])[C:15]([NH:22][C@@H:23]2[C:52](=[O:53])[N:25]3[C:26]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:37])=[C:27]([CH2:30][O:31][C:32](=[O:35])[NH:33][CH3:34])[CH2:28][S:29][C@H:24]23)=[O:17])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)C=C(C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=CC(C)C)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a mixture of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoic acid (1.56 g), diphenylmethyl 7β-amino-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.27 g), and N-methylmorpholine (2.0 ml) in dichloromethane (50 ml) is added diphenylphosphoryl chloride (1.27 g) at -30° C. After 2 hours, the reaction mixture is neutralized with 10% citric acid, washed, dried, and purified by chromatography give diphenylmethyl 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoylamino]-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.27 g). Yield: 73%.
Reaction SMILES: [CH3:1][C@@H:2]([C:5]([N:7]1[C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH2:3][SH:4].C(N(CC)C(C)C)(C)C.Cl[C:25]([O:27][CH2:28][Cl:29])=[O:26]>O1CCOCC1.O>[Cl:29][CH2:28][O:27][C:25]([S:4][CH2:3][C@@H:2]([CH3:1])[C:5]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:11]1[C:12]([OH:14])=[O:13])=[O:6])=[O:26]
Reactant: O=C(Cl)OCCl
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](CSC(=O)OCCl)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
Captopril (2.48 g, 0.0114 Mol) and N,N-diisopropyl ethylamine (4.50 ml, 0.0258 Mol) were dissolved in dioxane/H2O (30 ml, 1:1). The mixture was cooled to 0° C. and 1-chloromethyl chloroformate (1.20 ml, 0.0147 Mol) was added. The reaction was stirred at 0° C. for 4 h, then partitioned between HCl (4%, 30 ml) and CH2Cl2 (30 ml). The aqueous phase was extracted with CH2Cl2 (2×30 ml) and the combined organic phases were washed with HCl (4%, 30 ml) and brine (3×30 ml), dried over sodium sulphate and evaporated under reduced pressure affording 1-[(2S)-3-(chloromethoxycarbonyl)mercapto-2-methyl-1-oxopropyl]-L-proline as a clear oil (2.60 g) that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C(Cl)Cl.B(Br)(Br)[Br:31].O>CCOC(C)=O>[Br:31][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(CNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Into a 1-neck round-bottom flask were added [3-({5-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]methanol (0.66 g, 1.8 mmol) and 5 mL of methylene chloride. To the above mixture was slowly added a solution of boron tribromide in methylene chloride (2.7 mL, 2.7 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to room temperature (“rt”) and stirred overnight. The resultant mixture was cooled in a dry ice bath when water (10 mL) was added. The mixture was allowed to warm up to rt, followed by an addition of EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined and solvent removed under vacuum. The crude was purified by prep-HPLC to give the desired product (730 mg, 99%). LCMS for C18H17BrClN4O (M+H)+: m/z=418.9, 420.9. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 9.34 (br s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.68 (t, J=1.7 Hz, 1H), 7.41 (m, 1H), 7.16 (t, J=7.9 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 6.70 (m, 1H), 6.59 (m, 1H), 4.58 (d, J=6.6 Hz, 2H), 4.49 (s, 2H).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:19]1[CH2:21][C@@H:20]1[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>C1COCC1>[OH:19][CH2:21][C@H:20]1[CH2:22][C@@H:23]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CC[C@H]1CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)[C@H]1C[C@@H]1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
1.6M n-Butyllithium/hexane solution (76 mL, 120.98 mmol) was added dropwise to a solution of diisopropylamine (12.24 g, 120.98 mmol) in THF (240 mL) at 0° C. over 12 min under argon atmosphere. The mixture was stirred at 0° C. for 30 min, and the reaction mixture was cooled to −78° C. A solution of methyl (S)-3-(oxiran-2-yl)propanoate (13.12 g, 100.81 mmol) in THF (10 mL) was added dropwise thereto at −78° C. over 12 min. The reaction mixture was stirred at −15° C. for 2 hr, and poured into cooled 0.5N hydrochloric acid (600 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 49→70% ethyl acetate/hexane) to give methyl (1S,2S)-2-(hydroxymethyl)cyclopropanecarboxylate (2.27 g, 17.44 mmol, 17%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.S(O[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1)(=O)(=O)C>O>[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:21][CH2:22]1)=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CS(=O)(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
Sodium hydride (300 mg of a 60% suspension) was added to a stirred solution of 4-methylphenylsulphonamide and the mixture stirred at room temperature until effervescence had ceased. N-benzyloxycarbonylpiperidine-4-methanol mesylate (1.09 g) was added and the mixture heated at 100° C. for 7 hours. After cooling to room temperature it was diluted with water (200 ml) and extracted with ether (4×40 ml); the extracts were combined, washed with water (2×) and brine, dried (MgSO4) and evaporated to yield N-(1-benzyloxycarbonylpiperidin-4-ylmethyl)-4-methylphenylsulphonamide NMR (d6DMSO): δ0.8-1.1 (2H,m); 1.5-1.7 (3H,m); 2.35 (3H,s); 2.6 (2H,t); 2.7-2.9 (2H,m); 4.0 (2H,d); 5.0 (2H,s); 7.2-7.5 (7H,m); 7.55 (1H,t); 7.7 (2H,d); m/e 403 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:6]2[CH2:5][C:4]3([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[S:3][CH:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1NCC2(CCN(C)CC2)S1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1SC2(CCN(C)CC2)CN1S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (573 mg, 3.08 mmol) was dissolved in dry dichloromethane (2 ml) under an argon atmosphere. Distilled triethylamine (644 μl, 4.62 mmol) was added and the resulting solution was cooled to 0° C. A solution of p-fluorobenzenesulfonyl chloride (600 mg, 3.08 mmol) in dry dichloromethane (2 ml) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 1 h of stirring, dichloromethane (50 ml) was added and the resulted solution was washed with water (2×10 ml). The organic phase was dried with anhydrous magnesium sulfate, filtered and evaporated to give the crude mixture as an oil. The crude product was purified by flash chromatography (silica, CH2Cl2/MeOH/NH4OH 93/7/1) to provide AF716 (496 mg, 98.8% chemical purity) as an off-white powder. 1H NMR (CDCl3, 300 MHz) δ 7.89-7.85 (m, 2H, two CHCSO2), 7.27-7.19 (m, 2H, CHCF), 5.02 (q, J=6.12 Hz, 1H, CH—CH3), 3.66 (d, J=11.37 Hz, 1H, CHHNS), 3.48 (d, J=11.37 Hz, 1H, CHHNS), 2.72-2.50 (m, 2H, CH2NCH3), 2.25 (s, 3H, NCH3), 2.16-2.07 (m, 2H, CH2NCH3), 1.95-1.88 (m, 2H, CH2CS), 1.55 (d, J=6.12 Hz, 3H, CH3CH), 1.48 (m, 2H, CH2CS) ppm; 13C NMR (CDCl3, 300 MHz) δ 166.92 and 163.54 (C), 130.05 (CH), 129.93 (CH), 129.58 (C), 116.60 (CH), 116.30 (CH), 60.76 (C), 60.24 (CH), 54.05 (CH2), 53.22 (CH2), 46.03 (CH3), 37.16 (CH2), 37.05 (CH2), 25.56 (CH3) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[N:5]2[CH:31]=1.[Cl:32][C:33]([Cl:38])([Cl:37])[C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:21])([F:23])[F:22])(=[O:19])=[O:18])[N:5]2[C:31]=1[C:34](=[O:35])[C:33]([Cl:38])([Cl:37])[Cl:32]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cn2c(CN(CCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)cccc2n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccc(CN(CCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n2c1C(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 64.9 %

Procedure:
To a solution of 2.90 g (6.24 mmol) of 2-methyl-5-[N-tert-butoxycarbonyl-N-[4-(trifluoromethanesulfonamido)butan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 2.29 g (18.73 mmol) of 4-dimethylaminopyridine in 25 ml of chloroform was added dropwise, for 3 minutes, 2.1 ml (18.73 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 20 hours under reflux. The reaction mixture was then poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution and dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.47 g of the desired compound (65.2%, pale yellow liquid).