Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)=O.S(C)C>C1COCC1>[C:15]1([C@@:2]([NH2:1])([CH3:14])[CH2:3][CH2:4][NH:6][C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(NC(=O)C[C@@](C)(N)c2ccccc2)c1
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1cccc(NCC[C@@](C)(N)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A solution of (R)-3-amino-3-phenyl-N-m-tolylbutanamide (218 mg, 0.81 mmol) in THF (5 mL) was cooled to 0° C. under N2 and 2M BH3.Me2S (1 mL, 2 mmol) was added. Then the mixture was stirred at 80° C. overnight. The reaction mixture was quenched with MeOH and concentrated. The residue was purified by preparative TLC to afford (R)-3-phenyl-N1-m-tolylbutane-1,3-diamine (50 mg, 24%). 1H NMR (CDCl3): 1.59-1.62 (m, 7H), 1.30-1.35 (m, 4H), 2.15-2.20 (m, 3H), 2.40-2.65 (m, 2H), 2.98-3.05 (m, 2H), 3.35-3.45 (m, 1H), 3.60-3.65 (m, 6H), 3.75-3.80 (m, 1H), 6.40-6.60 (m, 2H), 6.90-7.01 (m, 1H), 7.25-7.40 (m, 4H), 7.45-7.52 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N#N.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]1[CH2:33][CH2:32][N:31]([CH3:34])[C:30]1=[O:35]>CN(C=O)C.C(Cl)(Cl)Cl.CO>[CH2:13]([O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH:29]2[CH2:33][CH2:32][N:31]([CH3:34])[C:30]2=[O:35])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCC(Br)C1=O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCN(C)C2=O)c1
Reaction time: 0.25 h

Procedure:
Methyl 3-hydroxy-5-(benzyloxy)benzoate (4.75 g) (CAS No. 54915-31-0] was dissolved in DMF in single necked round bottomed flask fitted with stop cock with N2(g) balloon. Potassium carbonate (8.4 g) was added and reaction was stirred for 15 min. 3-Bromo-1-methyl-pyrrolidine-2-one (4.91 g) (Intermediate 5) [J. Med. Chem., 1987, 30, 1995-98] was added to reaction mixture in three different portions at room temperature. The reaction was stirred at ambient temperature for 16 h and monitored by TLC using 10% methanol: chloroform as mobile phase. After 16 h, TLC showed completion of reaction mixture and formation of one polar spot. The reaction mixture was diluted with ice-cold water and extracted with EtOAc. All organic layers were combined and washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get crude thick liquid product. The crude product was purified by flash column chromatography. The desired product was eluted at 50% of EtOAc: Chloroform. Pure white solid was obtained after column purification (6.1 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1)[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][O:30][C:31](=[O:41])[CH2:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35](Br)[CH:34]=1>>[CH3:29][O:30][C:31](=[O:41])[CH2:32][C:33]1[CH:34]=[C:35]([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[CH2:9][N:3]([C:4]([CH:6]2[CH2:7][CH2:8]2)=[O:5])[CH2:1][CH3:2])[CH:36]=[C:37]([Cl:39])[CH:38]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: cyclopropanecarboxylic acid ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]amide and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3]1.[OH-].[Na+].Cl.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(O)C>[CH3:29][C:24]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[C:23]=1[N:30]1[CH2:31][CH2:32][N:33]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([N:6]3[CH2:5][CH2:4][O:3][C:2]3=[O:1])=[CH:17][CH:16]=2)=[O:13])[CH2:34][CH2:35]1
Reactant: Cc1cc(C)c(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(N2CCOC2=O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)c1
Temperature: 50 °C
Yield: 9.6 %

Procedure:
To ethyl 4-(-2-oxooxazolidin-3-yl)benzoate (0.235 g) described in Preparation Example 12 were added 1 M aqueous sodium hydroxide solution (1.3 mL) and ethanol (5 mL), and the mixture was stirred at 50° C. 1N hydrochloric acid (1.3 mL) was added, 1-(2,4,6-trimethylphenyl)piperazine (0.215 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (0.277 g) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by HPLC (ODS, 0.05% TFA aqueous solution-acetonitrile) to give the title compound (37.7 mg).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(F)c3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 3-fluoro-phenylhydrazine according to the method described for example 43. MS: M=411.1 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:30]([CH2:29][CH2:28][C:20]3[S:19][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[C:31]2=[O:32])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCc1nc2ccccc2s1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCc2nc3ccccc3s2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(2-benzothiazolyl)butanoate (1.5 eq., prepared in Synthetic Example 22) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(benzothiazol-2-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 178 to 179° C./DMF, wherein the product was purified through flash column chromatography and recrystallization.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH:11]([CH3:17])[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[N:9]3[CH:11]([CH3:17])[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1CCNC(=O)c2cc3cc(F)cc(Br)c3n21
Product: CC1CCNC(=O)c2cc3cc(F)cc(-c4ccccc4)c3n21

Procedure:
The title compound, grey solid (67 mg, 87%), MS (ISP) m/z=309.4 [(M+H)+], mp 232.5° C., was prepared in accordance with the general method of example 1 from (RS)-7-bromo-9-fluoro-5-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 3) (77.8 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:11]=[O:12])[NH:10][C:4]=2[CH:3]=1.CC1C=CC(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:12][CH:25]=[N:24][CH:23]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc2cnc(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cc2[nH]c(-c3cnco3)cc2cn1
Temperature: 65 °C
Yield: 79.3 %

Procedure:
6-Bromo-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (Preparation 138, 604 mg 2.68 mmole), TOSMIC (1047 mg, 5.37 mmole) and potassium carbonate (759 mg, 5.5 mmole) in methanol (30 mL) was stirred and heated at 65° C. for 110 minutes. The methanol was evaporated and the residue partitioned between ethyl acetate (50 mL) and water (20 mL). The layers were separated and the organic solution was washed with water and brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate to afford the title compound (561 mg, 79%). 1H-NMR (d6-acetone, 500 MHz): δ 7.02 (d, J=0.95 Hz, 1H), 7.60 (t, J=0.95 Hz, 1H), 7.62 (s, 1H), 8.30 (s, 1H), 8.67 (d, J=0.95 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])[CH:23]=[CH:24][C:25]=1[F:26]>>[F:26][C:25]1[CH:24]=[CH:23][C:22]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[CH:21][C:20]=1[C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: O=C(O)C=Cc1ccc(F)c(Br)c1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Product: Cc1cc2c(cc1-c1cc(C=CC(=O)O)ccc1F)C(C)(C)CCC2(C)C
Yield: 63.3 %

Procedure:
In a manner similar to that of Example 1(c) by reaction of 2.0 g (8.12 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid (prepared in Example 5(a) of the patent WO-97/33881) and 1.54 g (6.25 mmol) of 3-(3-bromo-4-fluorophenyl)acrylic acid, 1.45 g (63%) of the expected compound was obtained in the form of a beige powder having a melting point of 181°-183° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Sn](Cl)Cl.C(Cl)Cl>CO>[NH2:20][C:19]1[C:14]([NH:13][C@@H:10]2[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]2)=[CH:15][C:16]([S:23]([CH3:26])(=[O:24])=[O:25])=[N:17][CH:18]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ncc2N)CC1
Temperature: 80 °C

Procedure:
To a solution of cis-N-isopropyl-4-(2-(methylsulfonyl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (0.177 g, 0.460 mmol) in MeOH (2 mL) was added anhydrous tin (II) chloride (0.349 g, 1.842 mmol). The reaction mixture was heated at 80° C. for 3 hours and was concentrated under vacuum. The remaining residue was dissolved in EtOAc and washed with 1N aqueous NaOH followed by brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 0-100% 90/10/1 DCM/MeOH/NH4OH:DCM to afford cis-4-(5-amino-2-(methylsulfonyl)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (0.150 g, 92% yield). MS (ESI pos. ion) m/z: 355.2 [M+H].
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C([O:30][C:31](=O)[CH:32]=[C:33]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:56])[CH3:55])=[CH:49][CH:48]=1)[C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1)CCC>CCCCCC>[CH:40]1([C:37]2[CH:36]=[CH:35][C:34]([C:33]3[CH:32]=[C:31]([OH:30])[C:52]4[C:47](=[CH:48][CH:49]=[C:50]([NH:53][C:54](=[O:56])[CH3:55])[CH:51]=4)[N:46]=3)=[CH:39][CH:38]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CCCCOC(=O)C=C(Nc1ccc(NC(C)=O)cc1)c1ccc(C2CCCCC2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Product: CC(=O)Nc1ccc2nc(-c3ccc(C4CCCCC4)cc3)cc(O)c2c1
Temperature: 250 °C
Reaction time: 1 h

Procedure:
1.2 L of Dowtherm A was charged into a 2 L three neck round bottom flask equipped with a condenser, magnetic stirrer, thermocouple, heating mantle with a variable voltage controller, and a nitrogen inlet. The solvent was heated to 250° C. and 3-(4-acetylaminophenylamino)-3-(4-cyclohexylphenyl)-acrylic acid butyl ester 48 g (0.11 moles) was cautiously added in small portions. As portions were added gas was evolved and foaming occurred. Crystals of product began to form and adhere to the sides of the vessel. After all material had been added heating of the mixture was continued for 1 hour. The mixture was then cooled to room temperature and hexane added. A solid product was collected by vacuum filtration and washed with hexane. After drying in a vacuum oven, 35.7 g (90%) of product was recovered.
Reaction SMILES: [CH2:1]([C:19]([CH3:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:22][CH2:23][C:24]([CH2:33]O)([CH2:29][N:30]=[N+:31]=[N-:32])[CH2:25][N:26]=[N+:27]=[N-:28].N(CC1(CN=[N+]=[N-])COC(CCCCCCCCCC)(C)OC1)=[N+]=[N-]>>[N:30]([CH2:29][C:24]1([CH2:25][N:26]=[N+:27]=[N-:28])[CH2:23][O:22][C:19]([CH3:21])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:20][CH2:33]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NCC(CO)(CO)CN=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCCCC(C)=O
Agent: CCCCCCCCCCC1(C)OCC(CN=[N+]=[N-])(CN=[N+]=[N-])CO1
Product: CCCCCCCCCCCCCCCCCCC1(C)OCC(CN=[N+]=[N-])(CN=[N+]=[N-])CO1

Procedure:
The following compound was prepared analogously as described in Example 9, starting from methyl octadecyl ketone and compound 1. 5,5-Bis-(azidomethyl)-2-decyl-2-methyl-1,3-dioxane (compound 17).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1.C(N(CC)CC)C.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.C(Cl)(Cl)Cl.[OH-].[Na+]>[CH2:15]([N:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@@H]1CCN(Cc2ccccc2)C1
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
The compound (3R)-pyrrolidin-3-ol hydrochloride (2.2 g, 17.8 mM) was dissolved in dichloromethane (25.0 ml) and triethylamine (5.0 ml, 35.6 mM) was added at room temperature with constant stirring for 5 minutes. Benzyl chloride (2.5 ml, 21.4 mM) was added to it in one lot at the same temperature followed by refluxing for 15 hours. The reaction mixture was diluted with chloroform and 1N sodium hydroxide (15.0 ml) was added with constant stirring for 10 minutes. The organic layer was separated and washed with aqueous sodium bicarbonate and brine solution. It was further dried over anhydrous sodium sulphate and concentrated to get the title compound. Yield=44.4% (1.4 g, 7.9 mM).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@@H:11]1[N:16]([CH3:34])[CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(F)cc2F)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
Combine 10-((S)-3-[2-(2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (57.3 mg, 0.61 mmol), formaldehyde (11.7 μL, 0.14 mmol, 37% in water), and 1,2-dichloroethane (5.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (41.5 mg, 0.20 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue to give 54.4 mg (92%) of the title compound: mass spectrum (ion spray): m/z=452.9 (M+1).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][NH:11][CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38].Cl>CC#N.CCOC(C)=O>[CH:1]1([CH:7]2[CH2:12][N:11]([S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])(=[O:39])=[O:38])[CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNCC1C1CCCCC1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccccc2F)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To a solution of 3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (15.0 mg, 0.036 mmol, 1.0 equiv) in MeCN (0.2 mL) at room temperature, was added NaOH (0.40 mL, 1.5 N solution, 0.60 mmol, 16.7 equiv) and 2-fluoro-benzenesulfonyl chloride (11.4 mg, 0.059 mmol, 1.64 equiv). The mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 3 N HCl (0.3 mL), and then diluted with EtOAc (10 mL). The mixture was washed with water (5 mL), brine (5 mL), then dried (over Na2SO4), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (0.1% NH4OH) to give product (5.0 mg, 24%) as white solid. MS: 543 [M−H+]. 1H-NMR (400 MHZ, CDCl3): δ 1.12 (m, 3H), 1.34 (m, 1H), 1.45-1.90 (m, 7H), 2.70-2.87 (m, 2H), 3.34 (d, 1H), 3.60-3.70 (m, 2H), 3.95 (d, 1H), 4.18 (d, 1H), 7.13 (s, 1H), 7.21 (t, 1H), 7.27 (t, 1H), 7.30-7.40 (m, 3H), 7.51-7.61 (m, 3H), 7.83 (t, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[S:5][C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[Br-].[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[CH2:57][Zn+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[O:14]1[CH2:15][CH2:16][N:11]([C:4]2[S:5][C:6]([S:7]([NH2:10])(=[O:9])=[O:8])=[C:2]([CH2:57][C:48]3[CH:49]=[CH:50][C:51]4[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:47]=3)[N:3]=2)[CH2:12][CH2:13]1
Reactant: [Zn+]Cc1ccc2ccccc2c1
Reactant: NS(=O)(=O)c1sc(N2CCOCC2)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sc(N2CCOCC2)nc1Cc1ccc2ccccc2c1
Reaction time: 0.08 h

Procedure:
To a dried flask was added 4-bromo-2-morpholinothiazole-5-sulfonamide (194 mg, 0.591 mmol), THF (4.79 mL), palladium(II) acetate (1.33 mg, 0.00591 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (4.85 mg, 0.0118 mmol). The mixture was stirred for 5 minutes, and a 0.500 M solution of 2-napthylmethylzinc bromide in THF (4.14 mL, 2.04 mmol) was then added dropwise over 30 minutes. The reaction was stirred at room temperature for 1 hour and quenched with saturated ammonium chloride (10 mL). The reaction was extracted with ethyl acetate (2×25 mL) and the combined organic layers were washed with water (15 mL), dried and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→40/60) which gave a mixture of the desired product with residual 4-bromo-2-morpholinothiazole-5-sulfonamide. This material was purified by preparative reverse phase chromatography to give 51 mg (22% yield) of the title compound as a white solid. LC/MS (FA) ES+ 390. 1H NMR (400 MHz, DMSO-d6) δ: 7.85-7.77 (m, 4H), 7.71 (bs, 2H), 7.50-7.42 (m, 3H), 4.25 (s, 2H), 3.64-3.61 (m, 4H), 3.35-3.32 (m, 4H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:57])([F:56])[C:46]1[CH:47]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:49]=[CH:50][CH:51]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:53](=[O:54])[CH2:52][C:48]3[CH:49]=[CH:50][CH:51]=[C:46]([C:45]([F:56])([F:44])[F:57])[CH:47]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccc(C(F)(F)F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-(trifluoromethyl)phenylacetic acid (0.6 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-trifluoromethyl-phenyl)-acetamide (0.7 g, 70%) as a white solid: mp 156-158° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=5.36 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.09 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.67 (s, 2H), 4.74 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.52-7.82 (m, 7H), 8.77 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.84, 41.53, 48.83, 121.94, 123.12 (123.17, 123.22), 125.50 (125.56, 125.60, 125.66), 127.15, 128.68, 129.09, 129.23, 131.53, 133.19, 133.31, 134.61, 137.51, 138.99, 166.88, 167.40, 179.77, 170.00, 172.72; Anal. Calcd. for C23H18N3O5F3: C, 58.35; H, 3.83; N, 8.88; F, 12.04. Found: C, 58.13; H, 3.53; N, 8.83; F, 11.69.