Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][C@H:18]3[CH2:20][O:19]3)[C:10]=2[N:21]=1.[NH2:22][C@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1.C(OC(=O)N[C@@H]1CC(=O)NC1)(C)(C)C>O>[OH:19][C@@H:18]([CH2:17][CH2:16][N:11]1[C:12](=[O:15])[CH:13]=[N:14][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[N:21][C:10]1=2)[CH2:20][NH:22][C@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CC[C@H]3CO3)c2n1
Agent: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CC[C@H](O)CN[C@@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
In a mixed solvent (12 ml) of ethanol and water (9:1) were suspended 6-methoxy-4-{2-[(2S)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (290 mg, 1.17 mmol) and 6-[(4R)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (which was synthesized in the same manner as those of Reference Examples 20, 21 and 22, using the [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester synthesized with reference to WO2004/22536; 291 mg, 1.17 mmol). The obtained mixture was stirred in a sealed tube at 80° C. for 16 hours.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH:5](C)[C:4](=[O:10])[O:3]1.C(OC1NC(=O)C1)(=O)C.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:10])[O:3]1
Reactant: CC1C(=O)OC(C)(C)OC1=O
Agent: CC(=O)OC1CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.9 %

Procedure:
2,2,5-trimethyl-1,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45°-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (° C.) 78-83 d.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:28]1.O>C(Cl)(Cl)Cl>[Br:1][C:28]1[O:27][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]=1[CH:36]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(OC(C)(C)C)c1coc2ccccc12
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(OC(C)(C)C)c1c(Br)oc2ccccc12
Yield: 45.5 %

Procedure:
N-Bromosuccinimide (265 mg, 1.48 mmol) and 1,1′-Azobis(cyanocyclohexane) (20 mg, 0.06 mmol) were added to a solution of ethyl 2-(1-benzofuran-3-yl)-2-(tert-butoxy)acetate (20b) (340 mg, 1.23 mmol) in chloroform (5 mL). The reaction mixture was refluxed for 5 hours. Water (5 mL) was added and the mixture was extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95/05) to provide ethyl 2-(2-bromo-1-benzofuran-3-yl)-2-(tert-butoxy)acetate (20c) (200 mg, 0.56 mmol, 46%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][C:21]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: O=C1CN(c2nncc3cc(Br)ccc23)CCN1
Reactant: Cc1ccc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCNC(=O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A mixture of 4-(6-bromophthalazin-1-yl)piperazin-2-one (0.1 g, 0.3 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.09 g, 0.3 mmol), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (0.5 mL, 1.0 mmol). The mixture resulted was warmed up to 90° C. and stirred for 1 h under nitrogen. The mixture was cooled down to room temperature, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound (60 mg) as a pale yellow solid. Found MS (ES+): 362(M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:19](=[O:28])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:19](=[O:28])[N:20]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C(=O)NCc2ccccc2)CC(=O)N(Cc2ccccc2)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl 1-benzyl-3-(benzylcarbamoyl)-5-oxopyrrolidine-3-carboxylate obtained in Preparative Example 1 (2) (20 g) in dimethylformamide (20 mI) was added to a mixture of 60% sodium hydride (2.5 g) and dimethylformamide (60 ml) under ice-cooling After the mixture was stirred at room temperature for 1.5 hours, benzyl bromide (9.7 g) was added under ice-cooling and the mixture was starred for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried, concentrated and purified by silica gel column chromatography to give 16.3 g of the object compound as white crystals, melting point 112°-115° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)C(C)C)(C)C.[C:14]([C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([F:33])=[C:28]([CH:32]=2)[C:29]([OH:31])=O)[CH:19]=[N:20][CH:21]=1)#[N:15].O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:14]([C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([F:33])=[C:28]([CH:32]=2)[C:29]([N:3]([CH3:4])[CH3:2])=[O:31])[CH:19]=[N:20][CH:21]=1)#[N:15]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(C(=O)O)c2)c1
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(C#Cc2cncc(C#N)c2)ccc1F
Reaction time: 2 h
Yield: 63.3 %

Procedure:
Add N-(3-dimethylaminopropyl)-N-ethylcarbodiamide hydrochloride (120 mg, 0.62 mmol) to a mixture of dimethylamine hydrochloride (51 mg, 0.62 mmol), N,N-diisopropylethylamine (108 μL, 0.62 mmol), 5-(5-cyanopyridin-3-ylethynyl)-2-fluorobenzoic acid, (prepared as described in EXAMPLE 120), (150 mg, 0.56 mmol) and 1-hydroxybenzotriazole hydrate (76 mg, 0.56 mmol) in N,N-dimethylformamide (2 mL), and stir for 2 h. Dilute the reaction mixture with ethyl acetate and an aqueous saturated solution of sodium bicarbonate and separate the layers. Extract the aqueous phase once with ethyl acetate. Extract the combined organic phases once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 30:70 to 50:50 with ethyl acetate:hexanes, to give the title compound as a white solid (104 mg, 63%).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH:12]([Cl:14])[CH3:13]>C(O)C>[Cl:14][CH:12]([CH3:13])[CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2]
Reactant: CC(Cl)CBr
Reactant: Oc1ccccc1Br
Agent: [Na]
Solvent: CCO
Product: CC(Cl)COc1ccccc1Br
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added in about 0.5 hour a solution of 173.0 g of o-bromophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hours, cooled to 0°, and treated, dropwise, with 157.5 g of 1-bromo-2-chloropropane. The last addition requires about 1 hour. The mixture is stirred at 0° for about 2 hours and slowly warmed to reflux during about 2 hours, heated under reflux for about 2 hours, filtered from the precipitated sodium bromide, and the filtrate is concentrated in vacuo at 40° to give about 240.2 g of o-bromophenyl 2-chloropropyl ether as a mobile, colorless liquid.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)=[C:2]=[O:3].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CCCCCC>C1COCC1>[NH:8]1[C:9]2[C:5](=[C:4]([NH:1][C:2]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=3)=[O:3])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C=Nc1cccc2[nH]ccc12
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2[nH]ccc12
Reaction time: 3 h

Procedure:
The product of Example 80A (0.16 g, 1 mmol) in THF (3 mL) was treated with 4-(trifluoromethyl)benzylamine (0.19 g, 1.1 mmol) at ambient temperature. After stirring for 3 hours, hexane was added to the reaction mixture to precipitate the title compound as a solid. mp 178° C. 1H NMR (300 MHz, DMSO-d6) δ 4.43 (d, 2H), 6.53 (t, 1H), (6.98 m, 3H), 7.26 (t, 1H), 7.57 (d, 2H), 7.62 (d, 1H), 7.71 (d, 2H), 8.37 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 334 (M+H); Anal. Calcd. For C17H14N3F3O: C, 61.26; H, 4.23; N, 12.61. Found: C, 61.28; H, 3.83; N, 12.31.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].Cl.CN.C([O-])(=O)C.[Na+]>ClCCl.O>[C:1]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[CH:17][N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)Oc1ccccc1C=O
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Oc1ccccc1C=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
2-tert-Butoxybenzaldehyde (550 mg, 3.09 mmol) was treated with nitromethane (1167 μL, 21.6 mmol) at ambient temperature in a flask. Solid methylamine hydrochloride (133 mg, 1.98 mmol) and sodium acetate (162 mg, 1.98 mmol) were added and the colorless reaction mixture was stirred rapidly at ambient temperature. After 30 minutes, the reaction mixture started to turn yellow. After 16 hours, the reaction was very yellow and precipitate has formed. Water (20 ml) and dichloromethane (40 ml) were added and the layers partitioned. The dichloromethane layer was dried with sodium sulfate, filtered, and concentrated to provide the title compound (705 mg, 3.19 mmol, 103% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[O:22])[C:10]=2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[C:11](=[O:22])[C@H:10]2[F:23])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C2=C(F)C(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 4-(1-ethoxycarbonylcyclopropyl)-3-fluoro-1-[1-(S)-phenylethyl]-3-pyrrolin-2-one (587 mg, 1.85 mmol) in ethanol (5 ml) was added Raney nickel (R-100, 2 ml). Under a hydrogen atmosphere of 5 kg/cm2, the mixture was stirred at room temperature for 1 hour. Next, Raney nickel (R-100, 3 ml) was further added and stirring was continued under the same conditions for 2.5 hours. After eliminating the catalyst by filtering through celite (washed with ethanol), the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1) to obtain 382 mg (64.6%) of the title compound as a colorless oily substance. The 1H-NMR data of this compound agreed with the data of the compound obtained in Referential Example 10-2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([S:8]([NH:11][CH:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)(=[O:10])=[O:9])[CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.C([O-])(=O)C.[K+].[NH2:46][C:47]1[CH:52]=[N:51][C:50](Br)=[CH:49][N:48]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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]>[NH2:46][C:47]1[N:48]=[CH:49][C:50]([C:2]2[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([S:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)(=[O:10])=[O:9])[CH:7]=2)=[N:51][CH:52]=1
Reactant: O=S(=O)(NC1CCC(O)CC1)c1cc(Br)ccc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(Cl)c(S(=O)(=O)NC3CCC(O)CC3)c2)cn1

Procedure:
A suspension of 5-bromo-2-chloro-N-(4-hydroxy-cyclohexyl)-benzenesulfonamide (Intermediate DJ) (0.1 g, 0.27 mmol), bis(pinacolato)diboron (0.07 g, 0.29 mmol), Pd(dppf)Cl2.DCM (0.011 g, 0.014 mmol) and potassium acetate (0.04 g, 0.40 mmol) in DME (3 ml) is heated at reflux for 1.5 hours. Pd(dppf)Cl2.DCM (0.011 g, 0.014 mmol), 2-amino-5-bromopyrazine (0.05 g, 0.29 mmol), 2M Na2CO3 (1.5 ml) and DME (1 ml) are added and the reaction heated at reflux for 1 hour. The reaction mixture is purified by reverse phase column chromatography (C18, 0-100% MeCN in water −0.1% TFA) to yield a solid which was dried in vacuo at 45° C. overnight to yield the title compound. 1H NMR (400 MHz, DMSO-6) δ 8.60 (1H, d), 8.55 (1H, d), 8.14 (1H, dd), 8.00 (1H, d), 7.85 (1H, d), 7.67 (1H, d), 7.14-6.45 (2H, br hump), 3.30-3.24 (1H, m), 3.02-2.93 (1H, m), 1.73-1.68 (2H, m), 1.64-1.60 (2H, m), 1.33-1.23 (2H, m) 1.10-1.00 (2H, m); MS m/z 383 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:11])=[O:10])=[C:6]([NH:7][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CS(=O)c1ccc(Cl)cc1N
Product: CS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1

Procedure:
Following General Procedure B, C, the title compound was prepared from 5-chloro-2-(methylsulfinyl)aniline and benzenesulfonyl chloride.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:33](=[O:35])[CH3:34])=[CH:25][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (109 mg, 0.27 mmol) and Et3N (150 μL, 1.1 mmol) in CH2Cl2 (4 mL) was added acetic anhydride (40 μL, 0.4 mmol), and the resulting solution was then stirred at rt for 18 h. The resulting white suspension was partitioned between CH2Cl2 (150 mL) and satd. aq. NaHCO3 (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a viscous, colorless oil (93 mg, 92%). MS (ESI): mass calcd. for C21H21N3O2S, 379.14; m/z found, 380.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.44-7.36 (m, 3H), 7.33-7.24 (m, 3H), 4.78 (br m, 0.5H), 4.23 (m, 0.5H), 3.78-3.73 (br m, 2.5H), 3.56 (m, 1.5H), 3.32 (dd, J=9.3, 2.2 Hz, 0.5H), 3.27 (dd, J=11.4, 2.3 Hz, 0.5H), 3.01 (dd, J=9.1, 2.2 Hz, 0.5H), 2.84 (dd, J=9.7, 2.1 Hz, 0.5H), 2.77 (br d, J=9.9 Hz, 0.5H), 2.56 (dd, J=9.9, 1.2 Hz, 0.5H), 2.08 (s, 1.5H), 2.00 (s, 1.5H), 1.98 (br m, 0.5H), 1.91 (br m, 0.5H), 1.80 (br m, 0.5H), 1.66 (br m, 0.5H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[H-].[Na+].CI.[C:38](OCC)(=O)C>O1CCCC1>[CH3:38][N:15]([C:16](=[O:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:30])([F:29])[F:31])[CH:22]=1)[C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:3])=[O:33])=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cn1ccc2ccc(NC(=O)CCC#Cc3cccc(OC(F)(F)F)c3)cc21
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)CCC#Cc1cccc(OC(F)(F)F)c1)c1ccc2ccn(CC(=O)O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
{6-[5-(3-Trifluoromethoxy-phenyl)-pent-4-ynoylamino]-indol-1-yl}-acetic acid ethyl ester (50 mg, 0.11 mmol) was added to a suspension of sodium hydride (9 mg, 0.22 mmol) in tetrahydrofuran (1.5 ml) at 0° C. The mixture was stirred for 30 min at 0° C., methyl iodide (30 μl, 0.44 mmol) was added and stirring was continued for 14 h at ambient temperature. The suspension was cooled to 0° C., sodium hydride (13 mg, 0.33 mmol) and methyl iodide (45 μl, 0.66 mmol) were added and the mixture was stirred for 4 h at ambient temperature. Ethyl acetate was added, the solution was successively washed with brine, 1 N HCl/ice water 1/1 and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 42 mg (0.09 mmol, 82%) of the title compound as yellow solid.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].Cl.[Cl:6][C:7]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:34][C:33]3[CH:32]=[N:31][N:30]([CH3:35])[C:29]=3[NH:28][C:27]3[CH:36]=[CH:37][CH:38]=[CH:39][C:26]2=3)=[O:24])[CH:20]=[CH:19][C:8]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[Cl:6][C:7]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:34][C:33]3[CH:32]=[N:31][N:30]([CH3:35])[C:29]=3[NH:28][C:27]3[CH:36]=[CH:37][CH:38]=[CH:39][C:26]2=3)=[O:24])[CH:20]=[CH:19][C:8]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18]1)=[O:12]
Reactant: CCC=O
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)C3CCNCC3)c(Cl)c1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1CCC(C(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of propionaldehyde (0.29 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of piperidine-4-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide hydrochloride (Compound number 1109) (2.8 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=521.4
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][N:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]([OH:30])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O[N:51]1[C:55]2N=CC=[CH:59][C:54]=2N=N1.C(N)CC>CN(C=O)C.CO>[CH2:8]([N:15]1[C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:24]([CH3:27])=[N:25][N:26]=3)[C:18]=2[CH:17]=[C:16]1[C:28]([NH:51][CH2:55][CH2:54][CH3:59])=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3ccccc3)n12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCN
Solvent: CO
Product: CCCNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1
Reaction time: 0.03 h

Procedure:
To a solution of 6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid trifluoroacetate salt (0.013 g, 0.031 mmol, from Step 5) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.023 mL, 0.13 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.022 g, 0.059 mmol). After stirring for 2 minutes, 1-propanamine (0.011 mL, 0.13 mmol, Aldrich) was added. The reaction was stirred for 15 minutes, then was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.5 mg, 32%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6][CH:5]=1.CC(C[AlH]CC(C)C)C.C(Cl)(=O)C(Cl)=O.CS(C)=O>C1COCC1.C(Cl)Cl.C(N(CC)CC)C>[C:14]([O:13][C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[CH:5][N:6]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(C=O)cn1
Reaction time: 1 h

Procedure:
To a solution of methyl-6-(tert-butoxycarbonylamino)-nicotinate (2.20 g, 8.72 mmol) in anhydrous THF (50 mL), cooled to -30° C. was added DIBAL-H (1.0M in hexane, 34. 8 mL, 34.8 mmol) dropwise. After 1 h, 40 mL of a saturated solution of Rochelle salts was added and stirred vigorously for 10 h. The volatiles were removed in vacuo and the aqueous layer was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (1×50 mL) and brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was used directly in the next step. To a solution of oxalyl chloride (4.12 g, 32.46 mmol) in methylene chloride (30 mL), cooled to -78° C., was added DMSO (2.54 g, 32.46 mmol) dissolved in methylene chloride (9 mL) dropwise. After 20 minutes, the crude alcohol (1.82 g, 8.11 mmol) dissolved in 35 mL of methylene chloride was added followed by triethylamine (4.92 g, 48.66 mmoL). The ice bath was removed and the reaction stirred for 1 hr at rt, then water (30 mL) was added. The layers were separated and the aqueous layer was extracted with methylene chloride (2×50 mL). The organic layer was washed with water (1×50 mL) and brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (30×150 mm column of SiO2, EtOAc/methylene chloride 1:11) to give the title compound as a colorless solid: