Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:33]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:26]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]4=[O:33])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: O=C1CCCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCCCCC4=O)cc3F)CC2)c(C)c1
Yield: 19 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 111 and azepan-2-one (58 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (41 mg) was obtained.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15](=[O:20])[CH2:14][CH2:13]2.C(O)(=O)C>C1(C)C=CC=CC=1.O>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:3]([O:6][CH3:7])=[O:8])=[C:15]([OH:20])[CH2:14][CH2:13]2
Reactant: COC(=O)OC
Reactant: O=C1CCc2cc(F)ccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C1=C(O)CCc2cc(F)ccc21
Temperature: 0 °C
Yield: 102.1 %

Procedure:
12.66 g (316 mmol) of 60% sodium hydride in oil, 900 ml of toluene and 17.69 ml (210 mmol) of dimethyl carbonate are introduced into a 2 l reactor. The reaction mixture is stirred at reflux for 1 h. A solution of 19 g (115 mmol) of 6-fluoro-3,4-dihydro-1H-naphthalen-2-one in 350 ml of toluene is subsequently added. The reaction mixture is heated at reflux for 24 h. The reaction mixture is subsequently cooled to 0° C. and then acidified by addition of 114 ml of acetic acid. 114 ml of water are added and the separated organic phase is separated by settling and washed with two times 150 ml of water and then with 100 ml of a saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulphate and then concentrated under reduced pressure to result in 26.1 g of a product which is used as is in the following stage.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CN(C=O)C.[Cu]Br>[CH2:11]([C:6]1[C:5]2[C:4](=[O:13])[CH2:3][C:2]([CH3:1])([CH3:14])[CH2:10][C:9]=2[N:8]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:7]=1)[CH3:12]
Reactant: Clc1ncccn1
Reactant: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cn(-c2ncccn2)c2c1C(=O)CC(C)(C)C2
Reaction time: 24 h
Yield: 25 %

Procedure:
A solution of 6,6-dimethyl-3-ethyl-4,5,6,7-tetrahydro-1H-indole-4-one (100 mg, 0.52 mmol), K2CO3 (87 mg, 0.63 mmol), copper (I) bromide (15 mg, 0.1 mmol) and 2-chloropyrimidine (71 mg, 0.63 mmol) in DMF (1 mL) were heated at 180° C. for 24 h. More copper (I) bromide (16 mg, 0.1 mmol) and 2-chloropyrimidine (50 mg) were added and heating continued for a further 24 h. The DMF was evaporated and the residue partitioned between water and DCM. The organic layer was separated and the aqueous phase extracted with DCM (2×). The combined organic layers were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with 4:1 isohexane: EtOAc, to afford the title compound (35 mg, 25%) as a yellow solid. mp 111-114° C. Found: C, 71.07; H, 6.98; N, 15.20%. Calc C16H19N3O: C, 71.35; H, 7.11; N, 15.60%. 1H NMR (360 MHz, d6-DMSO) δ 1.06 (6H,s), 1.15 (3H,t, J=7.4 Hz), 2.30 (2H,s), 2.67 (2H,q, J=7.3 Hz), 3.23 (2H,s), 7.44 (1H,t, J=4.8Hz), 7.47 (1H,s), 8.86 (2H,d, J=4.8Hz). MS (ES+) 270 (+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC(C2CCC(C(OC)=O)C2)=CC=1>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: COC(=O)C1CCC(c2ccc(N)cc2)C1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(-c2ccc(N)cc2)cc1

Procedure:
Diethyl (4′-nitrobiphenyl-4-yl)malonate was reduced by the method of Intermediate 84, step (ii), to give the title compound; 1H NMR δ 1.17-1.22 (6H, m), 4.10-4.22 (4H, m), 4.92 (1H, s), 5.22 (2H, s), 6.63-6.66 (2H, m), 7.35-7.38 (4H, m), 7.52-7.54 (2H, m); MS m/e MH+ 328.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:20]=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl[C:57]1[C:58](=[O:69])[C:59](C#N)=[C:60]([C:65]#N)[C:61](=O)[C:62]=1Cl>C(Cl)Cl.O>[CH2:61]([CH:60]1[CH:65]([C:20]2[N:19]3[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:2])=[O:3])[C:15]=4[N:16]=[CH:17][C:18]3=[N:22][N:21]=2)[CH2:57][CH:58]([OH:69])[CH2:59]1)[CH3:62]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nncn23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1CC(O)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To 2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1.153 g, 2.11 mmol, prepared using Z from Preparation #EE.1, A from Example #1, Step D, HATU, and TEA, B with DIEA) in DCM (18 mL) and water (3.5 mL) was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (0.576 g, 2.54 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. The solid was removed by filtration while washing with DCM (150 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (2×40 mL) and brine (40 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified using silica gel chromatography (40 g) eluting with a gradient of 30-100% EtOAc in DCM to give 3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.672 g, 75%): LC/MS (Table 1, Method b) Rt=2.09 min; MS m/z: 426 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:46](=[O:47])[NH:45][C:42]4[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=4)[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(=O)Nc4ccc(F)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), 4-fluorophenyl isocyanate (0.023 mL, 0.205 mmol) was added. The mixture was stirred at room temperature for 4 h. It was then purified by HPLC to give the titled compound (32 mg). MS 521.5 (M+H); UV 204.1, 243.1 nm.
Reaction SMILES: Cl[Sn]Cl.O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=2)[CH2:16][CH2:17]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add SnCl2.H2O (11.8 mmol, 2.7 g) over a solution of 4-(5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.4 mmol, 0.8 g) in 20 mL of ethyl acetate. Stir the solution at room temperature overnight. Add aqueous NaHCO3 solution until the solution pH is basic and extract with ethyl acetate. Filter the suspension through a pad of Celite®. Combine the organic layers and wash with saturated aq. sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound. MS(ES): m/z=293 [M+H].
Reaction SMILES: Cl[C:2]1[N:6](COCCOC)[C:5]2[CH:13]=[C:14]([Cl:24])[C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:4]=2[N:3]=1.[NH:25]1[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[CH2:33]([O:32][C:30]([C:28]1[CH:29]=[N:25][N:26]([C:2]2[NH:6][C:5]3[CH:13]=[C:14]([Cl:24])[C:15]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:16][C:4]=3[N:3]=2)[CH:27]=1)=[O:31])[CH3:34]
Reactant: COCCOCn1c(Cl)nc2cc(Oc3ccccc3)c(Cl)cc21
Reactant: CCOC(=O)c1cn[nH]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc(Oc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 80 °C

Procedure:
To a stirred solution of 2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole (0.251 g, 0.684 mmol) and ethyl pyrazole-4-carboxylate (0.115 g, 0.820 mmol) in dry DMF (4 mL) was added anhydrous cesium carbonate (0.535 g, 1.64 mmol). The stirred suspension was heated in 80° C. bath in a sealed tube for 2 h. After coming to ambient temperature, the reaction mixture was added to ice water (100 mL), acidified with 1N HCl (3 mL) and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried, filtered, and concentrated under reduced pressure to afford the titled product as a crude orange paste (0.361 g). MS (ESI/CI): mass calcd. for C23H23ClN4O5, 470; m/z found, 471 [M+H]+.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=2[C:6]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.C1CCCCC1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[O:3][C:2]([N+:28]([O-:33])=[O:29])=[C:6]([C:7]3[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:17]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1cccc(-c2c([N+](=O)[O-])oc3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-bromo-5-chloro-3-benzofuranyl)phenylacetic acid in chloroform with 1.5 equivalents of cyclohexane is treated with 1.5 equivalents of dinitrogen tetroxide and stirred for about 20 hours at room temperature. The mixture is washed with water, extracted with saturated sodium bicarbonate solution, then the aqueous extracts are acidified. The mixture is extracted with dichloromethane, which is dried and concentrated. The residue is recrystallized from a mixture of benzene and hexane to provide 3-(5-chloro-2-nitro-3-benzofuranyl)phenylacetic acid.
Reaction SMILES: [CH2:1]([S:5]([N-:8][Si](C)(C)C)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:13]([O:17][C:18]([NH:20][C@H:21]([C:32](F)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C1C=CC=CN=1)C>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:5]([NH:8][C:32](=[O:33])[C@H:21]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)F
Reactant: CCCCS(=O)(=O)[N-][Si](C)(C)C
Agent: CN(C)c1ccccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
A solution of N-butanesulfonyl-N-trimethylsilylamide (0.75 g, 3.6 mmol), t-butoxycarbonyltryptophan fluoride (0.92 g, 3.01 mmol), and dimethylaminopyridine (37 mg, 0.3 mmol) in tetrahydrofuran (10 ml) is stirred at room temperature for 2 hours. The mixture is diluted with 10% citric acid and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude material is chromatographed on silica gel with ethyl acetate/hexane (1:1) and trace of acetic acid to give N-butanesulfonyl-(t-butoxycarbonyl)tryptophanamide.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([N:5]1[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:13]=[CH:14][O:15][C:7]=2[CH2:6]1)=O.B.O>C1COCC1>[F:17][C:2]([F:1])([F:16])[CH2:3][N:5]1[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:13]=[CH:14][O:15][C:7]=2[CH2:6]1
Reactant: O=C(N1CCC(O)c2ccoc2C1)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OC1CCN(CC(F)(F)F)Cc2occc21

Procedure:
7-Trifluoroacetyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]-azepin-4-ol prepared in the step 1 was dissolved in 1 mL of THF, a three molar equivalent of a solution of borane in THF was dropped thereinto under ice-cooling with stirring and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured over 1 mL of water followed by extracting with ethyl acetate. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The resulting residue was purified by silica gel column chromatography to give 23 mg of the objective compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13].CC(C)([O-])C.[Na+]>>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: COc1ccc(Cl)cc1
Reactant: CCCCNCCCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCN(CCCC)c1ccc(OC)cc1
Yield: 93.1 %

Procedure:
According to the general procedure B, 4-chloroanisole (150 mg, 1.05 mmol) reacted with N,N-di-n-butylamine (160 mg, 1.24 mmol) using 1 mol % of catalyst and sodium tert-butoxide (120 mg, 1.25 mmol) at 100° C. for 20 h to give the title compound (230 mg, 93%) as an colorless oil: 1H-NMR (400 MHz, CDCl3): δ 6.74 (d, 2H, J=9.2 Hz), 6.58 (d, 2H, J=9.2 Hz), 3.68 (s, 3H), 3.11 (t, 4H, J=8.0 and 7.2 Hz), 1.45 (m, 4H), 1.26 (m, 4H), 0.86 (t, 6H, J=7.6 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 150.96, 143.33, 114.79, 114.33, 55.82, 51.65, 29.46, 20.40, 14.02. GC/MS (EI): m/z 235 (M+), 235, 192, 150.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:3][CH2:4][N:5]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([OH:12])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>O1CCCC1>[F:1][C:2]1([F:27])[CH2:3][CH2:4][N:5]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:18])=[O:19])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:54]1[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]1)=[O:12]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(F)(F)/C(=C\C(=O)O)c3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(F)(F)/C(=C\C(=O)N3CCN(C)CC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 g of (Z)-(4,4-difluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene)acetic acid in 100 ml of tetrahydrofuran were added 4.12 g of 1-hydroxybenzotriazole, 5.85 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 3.36 ml of 1-methylpiperazine, followed by stirring for two hours at room temperature. After evaporation of the solvent, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of NaCl. After drying over magnesium sulfate, the solvent was evaporated off. The resulting residue was collected by filtration to give 11.76 g of (Z)-4,4-difluoro-5-[2-(4-methylpiperazin-1-yl)-2-oxoethylidene]-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzoazepine as a colorless amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[F:16][C:17]1[C:18]([CH3:40])=[C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=2)[C:20]([CH3:31])=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[F:16][C:17]1[C:18]([CH3:40])=[C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:1][C:2]3[CH:15]=[CH:14][C:5]4[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[CH:33]=2)[C:20]([CH3:31])=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)c(F)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.729 g, 3.50 mmol), {3′-fluoro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (1.28 g, 3.50 mmol) and tributylphosphine (1.13 g, 5.60 mmol) in a mixed solvent of toluene (45 mL) and tetrahydrofuran (5 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (1.41 g, 5.60 mmol) was added, and the mixture was stirred at room temperature for 4 hr under nitrogen atmosphere. Hexane (50 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20) and basic silica gel column chromatography (ethyl acetate:hexane=40:60-100:0), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (1.50 g, yield 77%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([N+:17]([O-])=O)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:17][C:13]1[C:14]([OH:16])=[N:15][C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1cnc(COCc2ccccc2)nc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(COCc2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of step B product, 3-d, (25 g, crude) in THF/H2O (1000 mL, VTHF/VH2O=1:1) was added with Na2S2O4 (33.3 g, 191.6 mmol) and stirred at room temperature for 4 h. The reaction mixture was extracted with EA (1000 mL), washed with brine (200 mL), and concentrated in vacuum. The residue was purified by column chromatography to afford the product, 3-e, (7.8 g) as a white solid. 1H NMR (300 MHz, CDCl3): δ 4.42 (s, 2H), 4.63 (s, 2H), 7.33-7.36 (m, 6H). LC-MS (M+H)+ 232.1
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][NH:32][CH2:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([N:32]([CH3:31])[C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:27][CH:26]=1)[CH3:34]
Reactant: CCNC
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added N-methylethanamine (0.025 mL, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The reaction was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (18 mg, 17% yield). m.p.=91.9° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.07 Hz, 3 H) 1.24 (br. s., 3 H) 1.85-2.04 (m, 3 H) 2.13-2.21 (m, 1 H) 2.43-2.48 (m, 3 H) 2.90 (s, 3 H) 3.14-3.22 (m, 4 H) 3.34-3.43 (m, 3 H) 3.54-3.64 (m, 1 H) 3.95-4.02 (m, 1 H) 6.92 (d, J=8.84 Hz, 2 H) 6.99 (d, J=2.02 Hz, 1 H) 7.25 (d, J=8.59 Hz, 2 H) 7.62 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:21]N)[CH:18]=[CH:19][CH:20]=1>CC(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:18]3[C:17](=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[NH:21][C:10]=2[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CSc1cccc(Br)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(3-Bromo-phenylsulfanyl)-propan-2-one (1.5 g, 6.12 mmol) and 3-chlorophenylhydrazine hydrochloride (1.21 g, 6.73 mmol) were combined in t-BuOH (50 mL) and the reaction was heated to 80° C. and stirred overnight. After cooling the reaction was worked-up using standard procedures to afford a crude mixture of two regioisomers which was then purified using silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.