Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2)#[CH:9]>[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:8]#[C:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:18]=[CH:17][CH:16]=2
Reactant: Brc1ccccn1
Reactant: C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3ccccn3)c21

Procedure:
Using Method J above, 2-bromopyridine (44.9 mg, 0.28 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 5) (50 mg, 0.19 mmol) using DPPFPdCl2 (7.7 mg) (Aldrich) and CuI (2 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent and heating at reflux for 2 days, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(2-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 30 mg, 47%).
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])=[CH:14][C:15]([CH3:20])([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.C(O)C>[C:1]([O:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([CH3:21])[CH2:14][C:15]([CH3:20])([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To an oven-dried 100 mL round-bottomed flask containing 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline (EXAMPLE 147) (200 mg, 0.69 mmol) in 50 mL 2:1 ethyl acetate/ethanol at rt was added 10% Pd on C (approx 1 mol %), and the mixture was stirred under an atmosphere of H2 for 4 h. The reaction mixture was then filtered, and concentrated under diminished pressure to give 201 mg (quant) of 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline as a white oily solid. Data for (R/S)-7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.02 (d, J=8.7, 1H, 5-H), 6.73 (br s, 1H, HNBoc), 6.39 (dd, J=8.3, 2.2, 1H, 6-H), 6.29 (br s, 1H, 8-H), 3.62 (br s, 1H, NH), 2.85 (ddq, J=12.5, 12.3, 6.4, 1H, 4-H), 1.70 and 1.39 [d of ABq, JAB=12.8, JA=5.5 Hz (3-Hequiv), JB=12.6 Hz (3-Hax)2H], 1.49 [s, 9H, (CH3)3CO)], 1.29 (d, J=6.7, 3H, 4-CH3), 1.21 (s, 3H, 2-CH3), 1-14 (s, 3H, 2-CH3).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl.Cl[C:9]([N:11]1[C:17]2[S:18][C:19]([CH2:21][CH3:22])=[CH:20][C:16]=2[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[N:14][CH2:13][CH2:12]1)=[O:10]>O1CCCC1>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:15]1[C:16]2[CH:20]=[C:19]([CH2:21][CH3:22])[S:18][C:17]=2[N:11]([C:9](=[O:10])[NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH2:12][CH2:13][N:14]=1
Reactant: CN(C)CCN
Reactant: CCc1cc2c(s1)N(C(=O)Cl)CCN=C2c1ccccc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N(C(=O)NCCN(C)C)CCN=C2c1ccccc1Cl
Temperature: 0 °C

Procedure:
To a solution of 7.1 g of 2-dimethylaminoethylamine in 40 ml of tetrahydrofuran is added 7.8 g of 1-chlorocarbonyl-5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride by portions with cooling and stirring. After the mixture is reacted for one and half hours at room temperature, the reaction substance is poured into 200 ml of ice-cold water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 5-o-chlorophenyl-7-ethyl-1-(2-dimethylaminoethylcarbamoyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloric monohydrate as yellow crystals. This product, when recrystallized from a mixture of methanol and ethyl acetate, melts at 160°-162° C with decomposition.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)C>[ClH:1].[F:31][C:28]1[CH:29]=[CH:30][C:25]([N:15]([CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)[C:16](=[O:24])[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(F)cc1)N(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccc(F)cc1)N(c1ccc(F)cc1)C1CCNCC1
Yield: 90.2 %

Procedure:
N-(1-Benzyl-4-piperidyl)-N-(4-fluorophenyl)-4-fluorobenzamide hydrochloride (3.2 g) in 95% strength ethanol (50 cc) is hydrogenated at 60° C. at atmospheric pressure in the presence of palladium hydroxide (0.5 g). After filtration through kieselguhr and concentration to dryness under reduced pressure (5.2 kPa), N-(4-fluorophenyl)-N-(4-piperidyl)-4-fluorobenzamide hydrochloride (2.3 g) is obtained in the form of a white powder, m.p. 170° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[OH-].[Ca+2:9].[OH-]>>[CH3:6][C:5]([O-:7])=[CH:4][C:1]([CH3:2])=[O:3].[CH3:6][C:5]([O-:7])=[CH:4][C:1]([CH3:2])=[O:3].[Ca+2:9]
Reactant: CC(=O)CC(C)=O
Agent: [Ca+2]
Agent: [OH-]
Product: CC(=O)C=C(C)[O-]
Yield: 108.4 %

Procedure:
1,202 g (12.0 mol) of acetylacetone was added to a 3 liter kneader equipped with a thermometer, a dropping funnel, a condenser and a jacket, and then stirred. Then 444 g [6 mol, calcium hydroxide/acetylacetone=1/2.0 (molar ratio)] of calcium hydroxide was added dropwise to the kneader over 3 hours. The reaction temperature was between 32 and 65° C. After completion of the dropping, the mixture was stirred and mixed at a temperature of 65 to 68° C. for 4 hours until the reaction was complete. The resulting product was warmed under a flow of nitrogen gas. At 68° C., the product was subjected to the drying step, and dried at 68 to 73° C. for 24 hours until the product attained a moisture content of 6.8% by weight. The dried product was cooled to give 1,550 g of yellowish white calcium acetylacetonate [yield 99.1 mol % (calcium hydroxide basis), purity 91.5% by weight].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:21][C:20]=1[CH2:19][O:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of acetic acid 3-hydroxyphenyl ester (5.0 g, 32.86 mmol) and potassium carbonate (6.8 g, 49.3 mmol) in DMF (40 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (6.8 g, 32.86 mmol) at RT. The reaction mixture is stirred for 3 h at RT followed by 24 h at 70° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 20% ethyl acetate in hexane to yield acetic acid-3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl ester as a clear oil.
Reaction SMILES: N(OC(C)(C)C)=O.NC1C=C([C@@H]2CNC(=O)C2)C=CC=1[Cl:15].Cl.[NH2:23][CH2:24][C@@H:25]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32](Br)[CH:31]=1)[CH2:26][C:27]([OH:29])=[O:28]>C(#N)C.C(OCC)(=O)C.[Cu](Cl)Cl>[ClH:15].[NH2:23][CH2:24][C@@H:25]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:15])[CH:31]=1)[CH2:26][C:27]([OH:29])=[O:28]
Reactant: NC[C@H](CC(=O)O)c1ccc(Cl)c(Br)c1
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Copper(II) chloride (0.183 g, 1.37 mmol) and tert-butyl nitrite (0.2 mL, 1.71 mmol) was stirred in acetonitrile (1 mL) at 0° C. (4R)-4-(3-Amino-4-chlorophenyl)pyrrolidin-2-one (0.24 g, 1.14 mmol) in acetonitrile (1 mL) was added dropwise. The mixture was warmed to 60° C. and stirred for 1 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with a 10% aqueous HCl solution, brine, and the ethyl acetate layers were concentrated. Hydrolysis of the resulting lactam with aqueous HCl as described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride provided the title compound. 1H-NMR (400 MHz, CD3OD): δ 7.53-7.54 (m, 1H), 7.51 (s, 1H), 7.26 (m, 1H), 3.28-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.77-2.83 (dd, J=16.4, 6.4 Hz, 1H) 2.63-2.69 (dd, J=16.8, 8.0 Hz, 1H); MS (ESI) m/z 247.99 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19]OC)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1>C(Cl)Cl>[C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][NH:33][C:34]4[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1cnc2sc(COC)nc2c1)c1ccccc1
Reactant: N#Cc1ccc(N)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1cnc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.54 g (3.85 mMol) of 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.3 ml (4.3 mMol) of a 1 molar solution of boron tribromide in methylene chloride was dissolved in a further 30 ml of methylene chloride and stirred for 5 hours at room temperature. Then the mixture was washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulphate and the solvent was distilled off. The crude product (1.9 g) was taken up in 15.0 ml of N,N-diisopropyl-ethylamine, mixed with 0.50 g (4.2 mMol) of 4-aminobenzonitrile and heated to boiling for one hour. Then the solvent was distilled off in vacuo, the crude product was taken up in 100 ml of methylene chloride, the organic phase was washed with 100 ml of water and dried with sodium sulphate. After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=35:65 to 1:1) and evaporated down again in vacuo. Yield: 0.45 g (24% of theory) of yellow amorphous solid, Rf value: 0.34 (silica gel; ethyl acetate/petroleum ether=1:1)
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:2]([CH:3]([CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=[O:1]
Reactant: COC(=O)c1ccc(CCC(CO)Cc2ccc(C(=O)OC)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(C=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 18.02 g (50.5 mmol) of dimethyl 4,4′-[2-(hydroxymethyl)butane-1,4-diyl]dibenzoate in 350 ml of dichloromethane is mixed with 13.07 g (60.6 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 12 hours. After conversion is complete, about 60 g of silica gel are added, and the solvent is removed in vacuo to dryness. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1→4:1). 14.73 g (41.46 mmol, 82% of theory) of a colourless oil are obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:49][C@@H:50]1[CH2:55][NH:54][CH2:53][C@H:52]([CH3:56])[NH:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:47][CH3:48])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:53][C@H:52]([CH3:56])[NH:51][C@H:50]([CH3:49])[CH2:55]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (40 mg, 0.062 mmol), (2R,6S)-2,6-dimethylpiperazine (70.73 mg, 0.619 mmol, 10 eq) and acetic acid (3.55 μL, 0.062 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in a VX-2500 Multi-Tube Vortexer overnight at room temperature. MP-triacetoxyborohydride (195 mg, 0.482 mmol, 7.78 eq) was then added and the mixture was stirred again in the VX-2500 Multi-Tube Vortexer overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on a Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. The reaction mixture was then purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on a Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 11.3 mg (27.2%) of the title compound. LC-MS m/z 744 (M+H)+, 1.41 min (ret time).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].Cl.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[F:35].C(N(CC)CC)C>ClCCl>[CH3:29][N:24]1[C:23]2[NH:22][C:21]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:20]=3[N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][NH:9][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[C:12]([F:35])[CH:13]=3)=[O:18])[CH2:28][C:27]=2[CH:26]=[N:25]1
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(C)ccc32)cc1F
Reaction time: 1 h
Yield: 51 %

Procedure:
1-Propanesulfonyl chloride (0.016 ml, 0.14 mmol) was added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (50 mg, 0.12 mmol) in dichloromethane (2 ml) and triethylamine (0.038 ml, 0.27 mmol) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white solid identified as the title compound (30 mg, 51%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[NH:25][NH2:26]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[NH:25][N:26]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccccc1C(F)(F)F
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1C(F)(F)F

Procedure:
ninhydrin, 4-(2-trifluoromethyl phenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=2[OH:20])(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[CH:1]1([NH:6][S:7]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[OH:20])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Yield: 91 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, (N-cyclopentyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.54 g, 1.7 mmol) was reduced with hydrogen and 10%,Pd/C (0.54 g) to form the desired product (0.45 g, crude). LC-MS m/z 291(M+).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:38][S:35]([C:32]3[CH:31]=[CH:30][C:29]([CH3:28])=[CH:34][CH:33]=3)(=[O:37])=[O:36])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and p-toluenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (42%); 1H NMR (CD3OD) δ 7.87 (d, J=8.2 Hz, 2H), 7.37-7.08 (m, 15H), 6.87 (d, J=8.2 Hz, 2H), 6.32 (d, J=15.7 Hz, 1H), 2.44 (q, J=7.4 Hz, 2H), 2.40 (s, 3H), 0.89 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[N:31]=[C:30]([C:32]#[N:33])[C:29](Br)=[CH:28][N:27]=1>>[NH2:25][C:26]1[N:31]=[C:30]([C:32]#[N:33])[C:29]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:24])=[CH:28][N:27]=1
Reactant: N#Cc1nc(N)ncc1Br
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B(O)O)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing (2′-(N-(tert-butyl)sulfamoyl)-3-fluoro-[1,1′-biphenyl]-4-yl)boronic acid and 2-amino-5-bromo-4-cyanopyrimidine. MS (ESI): mass calcd. for C21H20FN5O2S, 327.08; m/z found, 328.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.64-8.59 (m, 1H), 8.07 (dd, J=7.9, 1.4, 1H), 7.71-7.65 (m, 1H), 7.65-7.59 (m, 2H), 7.57 (s, 2H), 7.45-7.39 (m, 2H), 7.36 (dd, J=7.8, 1.7, 1H), 6.89 (s, 1H), 1.02 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:17])[C:6]=1[OH:19])=[S:4].O1CCCC1.[BH4-].[Na+]>CO>[CH3:1][NH:2][C:3]([C@H:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:17])([CH3:18])[C@H:6]1[OH:19])=[S:4]
Reactant: CNC(=S)C1=C(O)C(C)(C)Oc2ccc(C#N)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=S)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h
Yield: 7.1 %

Procedure:
To a mixture of 1.4 g of N-methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 15 ml of tetrahydrofuran, and 15 ml of methanol was added 0.23 g of sodium borohydride (NaBH4) at -10° C. with stirring, followed by stirring at -10° C. for 2 hours and then at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure, ice-water added to the residue, and the mixture made acidic with acetic acid and extracted with diethyl ether and ethyl acetate. The organic layer combined was dried over Na2SO4, followed by distillation. The residue was subjected to silica gel column chromatography (developing solution: CH2Cl2 :AcOEt=2:1). From the first fraction was obtained 0.1 g of cis-N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [NH2:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:8](=O)([O:14]C(C)(C)C)[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:9][C:8]([NH:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C[C@@H](N)CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
To a stirred suspension of (R)-3-aminobutanoic acid (2.415 g, 23.42 mmol) in dioxane (15 mL) and water (15.00 mL) was added TEA (4.90 mL, 35.1 mmol) dropwise. To the resulting light brown solution cooled at 0° C. was added portionwise di-tert-butyl carbonate (4.69 g, 26.9 mmol). The mixture was then stirred at rt for 16 hr. The reaction mixture was partitioned between water (80 mL) and EtOAc (80 mL). The separated aqueous layer was washed with EtOAc and acidified with 1 M aqueous KHSO4 to pH=3 and extracted with EtOAc (2×). The combined EtOAc extracts were washed with saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated to give (R)-3-(tert-butoxycarbonylamino)butanoic acid (4.301 g, 21.16 mmol, 90% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.92 (s, 1H), 4.14-3.96 (m, 2H), 2.56 (d, J=5.2 Hz, 2H), 1.45 (s, 9H), 1.25 (d, J=6.9 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[N:29]([CH2:30][CH2:31][O:32][C:33]4[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:34]=43)[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]>C(Cl)Cl>[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[C:34]4[CH:37]=[C:38]([S:41]([N:8]5[CH2:9][CH2:10][CH2:11][C@H:7]5[CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)(=[O:43])=[O:42])[CH:39]=[CH:40][C:33]=4[O:32][CH2:31][CH2:30][N:29]3[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCC[C@H]3CN3CCCC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-pyrrolidin-1-ylmethylpyrrolidine (36 mg, 0.23 mmol) and NEt3 (54 μL, 0.39 mmol) in DCM (5 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (64 mg, 0.08 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% 2M NH3/MeOH in DCM then C18, gradient 15-40% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 123 (22 mg, 56%). LCMS: RT 2.90 min [M+H]+ 512.3. 1H NMR (DMSO, 400 MHz): δ 9.01 (1H, d, J=2.40 Hz), 7.95 (1H, s), 7.82 (1H, s), 7.77 (1H, dd, J=8.65, 2.41 Hz), 7.26 (1H, d, J=8.65 Hz), 5.90-5.89 (1H, m), 4.61-4.60 (4H, m), 3.79-3.69 (1H, m), 3.42-3.41 (1H, m), 3.30-3.24 (1H, m), 2.76 (1H, dd, J=12.12, 4.10 Hz), 2.65-2.62 (5H, m), 1.80-1.79 (7H, m), 1.67-1.54 (1H, m). 1.59 (3H, d, J=6.62 Hz), 1.57 (3H, d, J=6.58 Hz)