Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.[CH2:7]([Li])CCC.[CH2:12]([O:19][C@@H:20]1[C@@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:23]([CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:22][C@H:21]1[C:51]1[CH:56]=[C:55]([CH2:57][O:58][CH3:59])[CH:54]=[C:53](Br)[CH:52]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+].C1C[O:66][CH2:65]C1>CN(C=O)C>[CH3:7][C:54]1[C:55]([CH2:57][O:58][CH3:59])=[CH:56][C:51]([C@H:21]2[C@H:20]([O:19][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@@H:25]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:42]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C@@H:23]([CH2:24][O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:22]2)=[CH:52][C:53]=1[CH:65]=[O:66]
Reactant: COCc1cc(Br)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(C=O)c1C
Reaction time: 0.5 h

Procedure:
A 1.6 M n-hexane solution of n-butyl lithium (14.0 ml) was added dropwise to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-bromo-5-(methoxymethyl)phenyl]-D-glucitol (7.8 g) in THF (5.0 ml) at −78° C. and the mixture was stirred for 30 minutes. DMF (1.0 ml) was added dropwise to the reaction mixture and the mixture was stirred for four hours. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain methyl 3-methoxymethyl-5-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzaldehyde (2.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[O:19])=[C:15]([O:28][CH3:29])[C:14]([O:30][CH3:31])=[C:13]([O:32][CH3:33])[CH:12]=2)=[O:10])=[N:6][CH:7]=1.Cl.[CH3:35][NH:36][CH2:37][CH2:38]N>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[N:36]([CH3:35])[CH2:37][CH2:38][N:27]=4)=[CH:22][CH:21]=3)=[O:19])=[C:15]([O:28][CH3:29])[C:14]([O:30][CH3:31])=[C:13]([O:32][CH3:33])[CH:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: COc1cc(C(=O)Nc2ccc(Br)cn2)c(NC(=O)c2ccc(C#N)cc2)c(OC)c1OC
Reactant: CNCCN
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)Nc2ccc(Br)cn2)c(NC(=O)c2ccc(C3=NCCN3C)cc2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of the compound of N-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}(4-cyanophenyl)carboxamide (680 mg, 1.33 mmol) in anhydrous methanol (5 ml) and ethyl acetate (10 ml) was saturated with hydrogen chloride gas at 0° C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the residue was dissolved in anhydrous methanol (5 ml) and N-methylethylenediamine (0.586 ml, 6.65 mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder (240 mg, 32%). MS found for C26H26BrN5O5 M+=568, (M+2)+=570.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:29])=O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([Cl:29])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
1.4 9 g of 5-bromo-2,4-dibenzyloxybenzoic acid, 40 ml of thionyl chloride and 1 drop of DMF are stirred at room temperature for 4 hours. The thionyl chloride is removed, and the residue is treated twice with dichloromethane, giving 9.4 g of 5-bromo-2,4-dibenzyloxybenzoyl chloride, which is processed further directly.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][CH3:37].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:27])[NH:39][C:35]([CH3:38])([CH3:34])[CH2:36][CH3:37])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: CCC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.3 g of the compound obtained in EXAMPLE 111 step B), 0.5 ml of 1,1-dimethylpropylamine, 0.5 ml of DIPEA, 0.35 g of BOP and 20 ml of DCM is stirred for 3 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl and with a 1N solution of NaOH and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 0.15 g of the expected product after crystallization from iso ether.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(OC(C#C)C)([C:16]1[CH:22]=CC(C)=[CH:18][CH:17]=1)(=O)=O>CN(C=O)C>[C:1]1(=[O:11])[N:5]([CH:17]([C:16]#[CH:22])[CH3:18])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C#CC(C)N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of potassium phthalimide (0.275 mole) in DMF (20 ml), 2-tosyloxy-3-butyne (0.25 mole) is added and allowed to react for 3 hours at 70° C. After cooling, the reaction mixture is extracted with chloroform and the chloroform layer is washed and dried. Removal of the chloroform, in vacuo, yields crude 2-phthalimido-3-butyne.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: OCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-aminoethanol according to general procedure 1 providing the intermediate (78 mg, 32%) as a white solid: Rf=0.41 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.73 (d, J=9.7 Hz, 1H), 3.80 (t, J=5.7 Hz, 2H), 3.52 (t, J=5.7 Hz, 2H); ES-MS: (M+H)=257, 259 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)[CH3:2].[I-].[NH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12)=[O:14])[CH3:2]
Reactant: N[n+]1ccccc1
Reactant: CCOC(=O)C#Cc1cccc(C)n1
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)c1c(-c2cccc(C)n2)nn2ccccc12
Yield: 24.1 %

Procedure:
A solution of (6-methyl-pyridin-2-yl)-propynoic acid ethyl ester (0.62 g, 3.3 mmol) and 1-aminopyridinium iodide (0.8 g, 3.6 mmol) in acetonitrile (15 mL) is treated with DBU (0.5 mL, 3.3 mmol) and heated to reflux for 0.5 hours. The reaction is concentrated to a dark solid and purified by silica gel column chromatography (1:1 hexane/ethyl acetate) to afford 0.224 g (24%) of desired product as a yellow solid. MS ES+ m/e 282.2 (M+1). UV (95% EtOH) λmax 275 nm (ε 13005), 234 nm (ε 26550), 225 nm (ε 26057). TOF MS ES+ exact mass calculated for C11H11NO2 (p+1): m/z=282.1243. Found: 282.1244. Anal. Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.04; H, 5.28; N, 14.65.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@H:15]([CH3:17])[C@H:14]([CH2:18][C:19]([OH:21])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: C[C@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Product: C[C@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)Nc1ccccc1
Yield: 89.1 %

Procedure:
A procedure similar to that described in Example 5 was carried out with cis-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (100 mg, 0.283 mmol) and aniline (28 μL, 0.311 mmol) to give 108 mg of the title compound (89%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.03 (s, 1H), 9.89 (s, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.27 (t, 2H, J=7.6 Hz), 7.19 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.02 (t, 1H, J=7.6 Hz), 5.16~5.26 (m, 1H), 2.70~2.85 (m, 2H), 2.63 (dd, 1H, J=14.2, 5.9 Hz), 2.24 (dd, 1H, J=14.2, 6.6 Hz), 2.10~2.26 (m, 1H), 1.13 (d, 3H, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[N:5][C:4](=[C:8](Cl)Cl)[N:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[NH2:14].[OH2:20].Cl>O1CCOCC1>[Cl-:1].[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[N:14]=[C:8]([C:4]1[NH:3][C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=1)[OH:20]
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: O
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: OC(=Nc1c(Cl)cccc1Cl)c1nc(Cl)c(Cl)[nH]1
Product: [Cl-]
Yield: 92 %

Procedure:
A solution of 109 g (0.5 mol) of 4,5-dichloro-2-dichloromethylene-imidazole in 125 ml of dioxane was added dropwise in the course of about 10-15 minutes to a mixture of 81 g (0.5 mol) of finely powdered 2,6-dichloroaniline, 500 ml of water and 75 g (about 0.75 mol) of 37% strength aqueous hydrochloric acid at 55°-60° C., while stirring. After stirring for about a further 2 hours, the product was filtered off, washed with water and dried. 159 g (92% of theory) of 4,5-dichloro-imidazole-2-carboxylic acid N-(2,6-dichlorophenyl)-imide-chloride were obtained. Long needles with a decomposition point of about 200° C. from acetonitrile or from chloroform.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:5][C:4]1=[O:15])[CH3:2].CC(C)([O-])C.[K+].[C:22]([S:30][CH2:31][C@H:32]([CH3:36])[C:33](Cl)=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:1]([N:3]1[CH2:7][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5]([C:33](=[O:34])[C@H:32]([CH3:36])[CH2:31][S:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]1=[O:15])[CH3:2]
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Reactant: CCN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)[C@H](C)CSC(=O)c2ccccc2)C1=O
Yield: 75.8 %

Procedure:
3.0 g of tert.-butyl (4S)-1-ethyl-2-oxo-imidazolidine-4-carboxylate, 1.6 g of potassium tert.-butoxide, (2S)-3-benzoylthio-2-methylpropionyl chloride (prepared from 3.2 g of (2S)-3-benzoylthio-2-methylpropionic acid and 10 ml of thionyl chloride) and 40 ml of tetrahydrofuran are treated in the same manner as described in Example 2-(2). Then, the oily residue obtained is purified by silica gel chromatography (Solvent, toluene-ethyl acetate(20:1)). 4.2 g of tert.-butyl (4S)-1-ethyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals.
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:10]1[CH:14]=[C:13]([C:15]#[N:16])[N:12]=[N:11]1)[C:5](OCC)=[O:6].[NH:18]([C:20]1[N:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:21]=1)[NH2:19].FC(F)(F)C(O)=O>O>[O:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:18]3[C:5](=[O:6])[C:4]([N:10]4[CH:14]=[C:13]([C:15]#[N:16])[N:12]=[N:11]4)=[CH:3][NH:19]3)[CH:21]=2)[CH2:27][CH2:28]1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)nn1
Reactant: NNc1cc(N2CCCOCC2)ncn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCCOCC4)ncn3)c2=O)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (0.9 mmol) of the compound from Example 7A, 178 mg (0.9 mmol) of the compound from Example 14A and 33 μl (49 mg, 0.4 mmol) of trifluoroacetic acid in 3 ml of water is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 80 mg (27% of theory)
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[CH2:11][O:12][CH3:13].[Br:14][C:15]1[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]2[O:22][C:21]([CH2:24][OH:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[CH3:27].O.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:14][C:15]1[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]2[O:22][C:21]([CH2:24][O:25][CH2:11][O:12][CH3:13])([CH3:23])[CH2:20][C:19]=2[C:26]=1[CH3:27]
Reactant: COCCl
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CO)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCOCC1(C)Cc2c(C)c(Br)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.8 %

Procedure:
Ethyldiisopropylamine (1.26 g, 9.74 mmol) and chloromethylmethylether (627 mg, 7.79 mmol) were serially added to a solution of THF (15 mL) containing (5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.85 g, 6.49 mmol) synthesized in Reference Example 123 under ice-cooling condition, and the mixture was warmed to room temperature and stirred for 15 hours. Ethyldiisopropylamine (1.26 g, 9.74 mmol) and chloromethylmethylether (523 mg, 6.49 mmol) were further added serially to the reaction solution under ice-cooling condition, and the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was poured into saturated sodium bicarbonate water, and THF was removed under reduced pressure, followed by extraction using ethyl acetate. The extract was washed with saturated saline and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 96:4-80:20) to give 1.62 g of the title compound as an oily product (yield: 76%).
Reaction SMILES: [N:1]([C@@H:4]([C@H:40]([C:48]1[CH:56]=[CH:55][C:51]2[O:52][CH2:53][O:54][C:50]=2[CH:49]=1)[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@@H:19]([CH2:22][O:23][C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6])=[N+]=[N-].CP(C)C>CCOC(C)=O.O>[NH2:1][C@@H:4]([C@H:40]([C:48]1[CH:56]=[CH:55][C:51]2[O:52][CH2:53][O:54][C:50]=2[CH:49]=1)[C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@@H:19]([CH2:22][O:23][C:24](=[O:31])[NH:25][CH2:26][C:27]([F:28])([F:30])[F:29])[N:18]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:17]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from step 2 (80 mg, 0.102 mmol) in EtOAc (8 mL) and water (2 mL), was added trimethylphosphine (0.5 mL, 1M solution in THF, 0.5 mmol). The reaction mixture was stirred at ambient temperature for 2 h, then diluted with water (20 mL) and extracted with EtOAc (25 mL×3). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound as colorless oil. This material was used in the next step without any additional purification. (M+H-Boc)+=682.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[CH3:31][S:32]([N:35]([C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][C@@H:51]2[CH2:53][O:52]2)[CH:44]=1)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:34])=[O:33]>C(Cl)(Cl)Cl.CO>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:53][C@H:51]([OH:52])[CH2:50][O:49][C:45]4[CH:44]=[C:43]([N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH:48]=[CH:47][CH:46]=4)=[CH:30][CH:29]=3)[CH2:17][CH2:16]2)=[O:19])=[CH:27][CH:26]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N(c1cccc(OC[C@@H]2CO2)c1)S(C)(=O)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CC(C)(C)OC(=O)N(c1cccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccc(F)cc4)CC3)cc2)c1)S(C)(=O)=O

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide formate (0.591 g, 1.42 mmol) was reacted with tert-butyl methylsulfonyl{3-[(2S)oxiranylmethoxy]phenyl]carbamate (0.488 g, 1.42 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give tert-butyl 3-{[(2S)-3-({4-[(1-{[(4-fluorobenzyl)amino]carbonyl}-4-piperidinyl)amino]phenethyl}amino)-2-hydroxypropyl]oxy}phenyl(methylsulfonyl)carbamate which was dissolved in formic acid and stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol) to furnish the title compound (0.1 g, 0.163 mmol).
Reaction SMILES: [C:1]1([C:7]2[CH:21]=[CH:20][C:10]3[N:11]=[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C>[CH3:33][S:34]([CH:14]([C:12]1[S:13][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:21]=[CH:20][C:10]=2[N:11]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(c1nc2ccc(-c3ccccc3)cc2s1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Ethyl 2-(6-phenylbenzo[d]thiazol-2-yl)acetate (described in WO2011/074560, 550 mg, 1.9 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. DBU (0.61 mL, 4.1 mmol) was added. After 10 minutes, methanesulfonyl chloride (0.2 mL, 3 mmol) was added dropwise. The reaction mixture was removed from the ice bath and stirred at room temperature. After 4 hours, the reaction mixture was cooled back to 0° C., and additional methane sulfonyl chloride (0.11 mL, 1.4 mmol) was added. Following addition, the reaction mixture was removed from ice bath and stirred at room temperature. After 3 days, the reaction mixture was quenched by the addition of water (20 mL), and the resulting solid was collected by filtration. The solids were dissolved in DCM, washed with aqueous 10% LiCl, 1N HCl, brine, dried over MgSO4, concentrated under reduced pressure, and purified by silica gel chromatography (eluting with 0-20% DCM/MeOH) to give Compound B1a (250 mg, 36% yield) as a yellow oil. HPLC: RT=1.03 min (LCMS Method O). MS (ES): m/z=376.0 [M+H]+. 1H NMR (400 MHz, pyridine-d5) δ 8.07 (br. s., 1H), 7.79-7.64 (m, 4H), 7.51 (t, J=7.7 Hz, 2H), 7.40 (s, 1H), 4.39 (d, J=7.0 Hz, 2H), 3.49 (s, 3H), 1.29 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:44][S:45]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(C(=O)NCCN2CCC(NS(C)(=O)=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise methanesulfonyl chloride (0.08 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature. The mixture was filtered and the filtrate was evaporated to 0.401 g oil. Flash chromatography [silica gel, methylene chloride/methanol (90/10)] yielded 0.147 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.149 g colorless crystals. Mp 204° C. Mass spectrum, m+ =407. Exact mass theory, 408.2069; found, 408.2066.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].B(F)(F)F.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:30])=[C:14]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:20][CH:19]=2)=O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:30])=[C:14]([C:16]2([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:22][CH:23]=3)[S:4][CH2:1][CH2:2][S:3]2)[CH:15]=1
Reactant: O=C(c1ccc(OCC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Reactant: SCCS
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)COc1ccc(C2(c3cc(Br)ccc3Cl)SCCS2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At 0° C., ethane-1,2-dithiol (3 mL) and BF3.2HOAc (4.8 mL) were added into a solution of (5-bromo-2-chlorophenyl)(4-(2,2,2-trifluoroethoxy)phenyl)methanone (5.0 g) in dry DCM. The mixture was stirred at room temperature for 12 hours. The mixture was added with saturated Na2CO3 aqueous solution and then extracted with DCM. The organic phases were combined, dried over Na2SO4, and concentrated to obtain the crude product, then the crude product was purified by silica-gel column chromatography (PE/EA=200/1) to obtain 4 g of 2-(5-bromo-2-chlorophenyl)-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3-dithiolane.