Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
A mixture of 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (100 mg, 0.26 mmol), tert-butyl 4-aminobenzoate (50 mg, 0.26 mmol), 1-methyl-1H-imidazole (85 mg, 1.02 mmol) and EDCI (200 mg, 1.02 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. Ethyl acetate (10 mL) and water (10 mL) were added to the mixture and the organic layer was washed with brine (10 mL×2) then dried over Na2SO4. The residue was concentrated and purified by chromatography (dichloromethane:MeOH=50:1) to give tert-butyl 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)benzoate (80 mg, 55%) as a yellow solid. LC-MS: [M+H]+, 567, tR=1.820 min
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH2:14]([NH2:16])[CH3:15].O>CC#N>[Cl:13][C:4]1[CH:3]=[C:2]([NH:16][CH2:14][CH3:15])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CCN
Solvent: CC#N
Solvent: O
Product: CCNc1cc(Cl)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (4.4 g, 20 mmol) in CH3CN (50 mL) was added dropwise a solution of ethylamine in water (65%, 2.7 g, 39 mmol) at 0° C., then the resulting mixture was stirred at RT overnight. The reaction was concentrated and the residue was washed with water to give ethyl 6-chloro-4-(ethylamino)nicotinate (3.9 g, 91% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1 H), 8.08 (s, 1 H), 6.53 (m, 1 H), 4.19 (q, J=7.2 Hz, 2H), 2.78 (q, J=7.2 Hz, 2 H), 1.28 (t, J=7.2 Hz, 3 H), 1.13 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 229.1[M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C[C:34]([N:36](C)C)=O>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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:34]#[N:36])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 1-chloro-7-(2-dimethylamino-benzooxazol-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (92 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.01 mmol), 1,1′-bis(diphenylphosphino)ferrocene (11 mg, 0.02 mmol), zinc cyanide (14 mg, 0.12 mmol), zinc (2 mg, 0.02 mmol) and dimethylacetamide (0.5 mL) was stirred at 120° C. for two hours before it was cooled to room temperature, partitioned between ethyl acetate and water, and filtered. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (32 mg): MS: (+) m/z 447.00 (M+1); (−) m/z 445.20 (M−1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:23][CH:24]=[O:25])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Product: O=CC=Cc1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyridinyl)benzaldehyde (prepared as described in Reference Example 11) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCCC1.O>[C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)O)C2C(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (6 g, 12 mmol) is dissolved in a mixture of 120 ml Tetrahydrofuran and 78 ml Water. LiOH.H2O (1 g, 24 mmol) is added. After 45 min., more Water (15 ml) is added and the reaction solution is stirred at room temp. for 24 h. The solvent is evaporated and the remaining solid is resolved in Water/Diethylether. The water layer is acidified to pH 1. The organic phase is separated and the water phase is extracted twice with Ethylacetate. The combined organic fractions are dried with MgSO4 and filtered. The solvent is evaporated to afford the product: Cal. 412.5, found (M)+ 412.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH2:25]([C@H:27]1[CH2:32][N:31]([CH:33]2[CH2:36][O:35][CH2:34]2)[CH2:30][CH2:29][N:28]1[C:37]1[CH:38]=[CH:39][C:40]([NH:43][C:44]2[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:49]=2)=[N:41][CH:42]=1)[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[CH:11]=[C:10]3[N:17]([CH2:18][CH2:19][N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:48]5[CH:49]=[C:44]([NH:43][C:40]6[CH:39]=[CH:38][C:37]([N:28]7[CH2:29][CH2:30][N:31]([CH:33]8[CH2:34][O:35][CH2:36]8)[CH2:32][C@@H:27]7[CH2:25][CH3:26])=[CH:42][N:41]=6)[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=5)[CH:7]=[CH:6][N:5]=4)[C:9]3=[O:22])[C:16]=2[CH2:15]1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with (4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde) 108a (280 mg, 0.8 mmol), (S)-3-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 161f (500 mg, 0.96 mmol), Pd(dppf)Cl2 (33 mg, 0.040 mmol), K3PO4 (360 mg, 1.6 mmol), sodium acetate trihydrate (240 mg, 1.6 mmol), and acetonitrile (100 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 164a (320 mg, 60%) as a yellow brown solid. MS-ESI: [M+H]+ 677.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([C:13]([O:15]C)=[O:14])[CH2:9][CH2:8]2.P([O-])([O-])([O-])=O.Cl.CC(=O)OCC(COC(=O)C)OC(=O)C.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2
Reactant: COC(=O)C1CCc2cccc(OC)c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CC(=O)OCC(COC(C)=O)OC(C)=O
Product: COc1cccc2c1C[C@H](C(=O)O)CC2
Reaction time: 6.5 h
Yield: 43.2 %

Procedure:
0.743 g (0.0034 mol) of methyl 8-methoxy-1,2,3,4-tetrahydro-2-naphthoate is dissolved in 26 ml of tert-butanol, and 75 ml of phosphate buffer at pH 7 are added to the solution prepared in this way. The pH of the solution, which rises to 7.3-7.5, is lowered to 7.1 by the addition of 1 N HCl. 0.836 g of Sigma PPL enzyme (known as porcine pancreatic lipase type II, crude, Sigma L-3126 - 46 U/mg using triacetin) is added to the mixture. The pH tends to drop as the reaction progresses, but is kept constant by the addition of a 0.25 N solution of NaOH, the pH being controlled by an automatic titration apparatus. After 6.5 hours, the mixture is poured into a 5% solution of sodium bicarbonate in order to stop the reaction by inactivation of the enzyme. Extraction is carried out with ethyl ether and the two phases are separated. The organic phase contains the unreacted ester principally of (S) configuration, which can be recovered as indicated in Example 10 below. The aqueous phase is acidified with 10% sulfuric acid and extracted with chloroform; the organic phase is filtered on Celite and dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 0.303 g of the title acid, which is crystallized from isopropyl ether. ee 95.2% (HPLC performed under conditions (d)); m.p. 137°-138° C.; [α]D25 =+54.6° (c=1.4%, CH3OH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[CH2:6][CH2:5]2.[CH2:15](OB(C=C)OCCCC)[CH2:16]CC.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1.O>[N+:11]([C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:14])=[CH:3][C:2]=1[CH:15]=[CH2:16])([O-:13])=[O:12]
Reactant: C=CB(OCCCC)OCCCC
Reactant: O=C1CCc2cc(Br)c([N+](=O)[O-])cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Yield: 77 %

Procedure:
A solution of 5-bromo-6-nitro-indan-1-one (58 mg, 0.23 mmol), (J. Med. Chem., 2003, 46, 399-408), vinylboronic acid dibutyl ester (74 μL, 0.34 mmol), Pd(PPh3)2Cl2 (7.8 mg, 0.0011 mmol), and Na2CO3 (167 mg, 1.57 mmol) in 4:1 THF/H2O (1.4 mL/360 μL) was heated to 80° C. overnight. The crude reaction was filtered over Celite and extracted with EtOAC. The organic phase was dried (MgSO4), filtered, and concentrated. The crude material was chromatographed (SiO2) to afford 36 mg (79%) of 6-Nitro-5-vinyl-indan-1-one; LC/MS calculated for [M+H]+ C11H9NO2: 204.1, found: 204.1.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][CH:10](OC)[CH2:11][CH:12](OC)OC.[F:19][C:20]([F:26])([F:25])[S:21][CH2:22][C:23]#[N:24]>[Cl-].[Cl-].[Zn+2]>[C:23]([C:22]([S:21][C:20]([F:26])([F:25])[F:19])=[CH:12][CH:11]=[CH:10][O:9][CH3:8])#[N:24]
Reactant: COC(CC(OC)OC)OC
Reactant: N#CCSC(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: COC=CC=C(C#N)SC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.3 %

Procedure:
A solution of acetic anhydride (52 mL), 1,1,3,3-tetramethoxypropane (26.4 g, 0.16 mL), trifluoromethylthioacetonitrile (14.5 g, 0.1 mol) and ZnCl2 (1 g) was heated at reflux. After 18 hours, the mixture was distilled up to 100° at atmospheric pressure. The residue was then cooled to 25° C. and filtered. The clear solution was distilled to yield 3.5 g of 4-cyano-4-trifluoromethylthio-3-butenealdehydedimethylacetal (bp 65°-93° C. at 18 mm) and 5.3 g of 1-cyano-1-trifluoromethylthio-4-methoxy-1,3-butadiene (bp 83°-105° C. at 0.5 mm). This material was combined and used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=1)([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=1)=[O:18]
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)NN(C(=O)CCc2ccccc2-c2cccc(C)c2C)C(C)C)cc1
Yield: 15.3 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (110 mg, 0.44 mmoles) and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (100 mg, 0.40 mmoles) in DMF (3 mL) was treated with triethylamine (0.16 mL, 1.19 mmoles), HOBT (64 mg, 0.48 mmoles) and EDCI (91 mg, 0.48 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product (30 mg, 16%). LC-MS m/e 489.40 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:14](=[O:15])[CH2:13][CH2:12][Cl:11])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: c1ccccc1
Product: O=C(CCCl)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Nitroaniline (0.3 moles), β-chloropropionyl chloride (0.35 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 4 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(3-nitrophenyl)-β-chloropropionamide as the residue.
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[CH:3]1[Br:23].N12CCCCC1C=NCCC2.O>CN(C)C=O>[Br:23][C:3]1[C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=2[N:6]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]=1
Reactant: O=C(N1c2ccccc2C(Br)C(Br)c2ccccc21)C(F)(F)F
Agent: C1=NCCCN2CCCCC12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N1c2ccccc2C=C(Br)c2ccccc21)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of 138.1 g of 10,11-dibromo-10,11-dihydro-5-(trifluoroacetyl)-5H-dibenz[b,f]azepine in 580 ml of dimethyl formamide is treated at 0°-10° C with 114.5 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene and stirred for 1 hour at the same temperature. The dark solution is then poured into a mixture of water and ice and the resultant suspension is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation, to yield crude, syrupy 10-bromo-5-(trifluoroacetyl)-5H-dibenz[b,f]azepine which is directly processed further.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[C:18]([CH3:20])=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.1) (200 mg, 0.50 mmol) and commercially available 3-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 221290-14-8] (155 mg, 0.60 mmol) according to the general procedure II. Obtained as a light yellow solid (275 mg, 97%). MS (ISP) 530.1 [(M+H)+]; mp 133° C. (dec).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:13])[CH:7]=[CH:6]2.[F:14][C:15]1[CH:16]=[C:17]([OH:29])[CH:18]=[C:19]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.CCOC(C)=O.O>[Cl:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][O:29][C:17]3[CH:18]=[C:19]([C:21]4([O:27][CH3:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:20]=[C:15]([F:14])[CH:16]=3)[CH:4]=2)[N:9]=1
Reactant: Clc1ccc2cc(CBr)ccc2n1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC1(c2cc(F)cc(OCc3ccc4nc(Cl)ccc4c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Bromomethyl-2-chloro-quinoline (2.5 g, 9.7 mmol), 3-fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenol (9a, 2.2 g, 9.7 mmol), and cesium carbonate (4.7 g, 14.6 mmol) were combined in MeCN (25 mL) and stirred at room temperature for 2 hours. The reaction was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the desired product, 9b.
Reaction SMILES: [C:1]([CH:4](/[CH:8]=[CH:9]\[F:10])[C:5](O)=[S:6])(=[O:3])[NH2:2].[NH2:11][C@H:12]1[CH2:16][O:15][N:14]([C:17]2([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:21][CH2:20][C:19](=[O:22])[O:18]2)[C:13]1=[O:39]>>[C:1]([CH:4](/[CH:8]=[CH:9]\[F:10])[C:5]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:17]2([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:21][CH2:20][C:19](=[O:22])[O:18]2)[C:13]1=[O:39])=[S:6])(=[O:3])[NH2:2]
Reactant: NC(=O)C(/C=C\F)C(O)=S
Reactant: N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O
Product: NC(=O)C(/C=C\F)C(=S)N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O

Procedure:
A procedure similar to Example 1 (a), using 179 mg of (Z)-2-carbamoyl-2-fluorovinylthioacetic acid and 356 mg of benzhydryl ester of a deacetyl compound of TAN-588, gave 358 mg of benzhydryl 2-{(4S)-4-[(Z)-2-carbamoyl-2-fluorovinylthioacetamido]-3-oxo-2-isoxazolidinyl}-5-oxo-2-tetrahydrofurancarboxylate.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]([CH2:18][CH3:19])[CH2:12][C:13]#[C:14][C:15]([OH:17])=O)[CH3:10].CN1CCOCC1.N#N.[NH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]2[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Br:49])[CH:44]=1>N1C=CC=CC=1>[Br:49][C:45]1[CH:44]=[C:43]([NH:42][C:33]2[C:32]3[C:37](=[CH:38][CH:39]=[C:30]([NH:29][C:15](=[O:17])[C:14]#[C:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:18][CH3:19])[CH:31]=3)[N:36]=[CH:35][C:34]=2[C:40]#[N:41])[CH:48]=[CH:47][CH:46]=1
Reactant: CCN(CC)CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CCN(CC)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Isobutyl chloroformate (0.261 g, 1.91 mmol) was dropwise added into an ice cold solution of 4-diethylamino-2-butynoic acid (0.456 g, 2.94 mmol) and N-methylmorpholine (0.294 g, 2.94 mmol) in 50 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 3 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.2 g (28.5%) of pale greenish yellow solid; ESMS m/z 476.2, 478.2 (M+H+); mp 133-135° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][S:21][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][S:9]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CSc2ccc(F)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cccc(CSc2ccc(F)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide (91 mg, 0.199 mmol) was dissolved in MeOH (2 ml). Zn (322 mg, 4.967 mmol) and NH4Cl (1 ml) was added to the solution. After the mixture was stirred for 30 min at room temperature, the solid was filtered and the filtrate was concentrated in vacuo and then the crude residue was purified by column chromatography (0→30% EtOAc in hexane) to afford the title product (50 mg, 59%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[CH2:16][OH:17])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:8]([CH2:16][OH:17])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(CO)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
[2-(Morpholin-4-yl)-5-nitrophenyl]methanol (1.38 g, 5.80 mmol) was hydrogenated using ammonium formate (3.67 g, 58 mmol) and Pd/C (10% Pd, 0.62 g, 0.58 mmol) in 50 mL of EtOH. The mixture was stirred for 1 h at room temperature and then filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in DCM and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated to yield expected compound as a brown powder (1.21 g, 99% yield). LC-MS: m/z (ESI) 209.2 [M+H]+. 1H NMR (300 MHz, MeOH-d4) δ7.02; (d, J=15.0 Hz, 1H), 6.83; (d, J=9.0 Hz, 1H), 6.68; (dd, J=6.0 Hz, 1H), 4.71; (s, 2H), 3.82; (t, J=4.5 Hz, 4H), 2.87; (t, J=4.7 Hz, 4H).