Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.[C:42]([O:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][S:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:51](O)=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]>O1CCCC1>[C:42]([O:46][C:47](=[O:48])[NH:49][C@@H:50]([CH2:54][S:55][S:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:51]([NH:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:52])([CH3:44])([CH3:45])[CH3:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (2.52 g, 6.62 mmol), benzylamine (0.723 ml, 6.62 mmol) and N,N-diisopropylethylamine (1.153 ml, 6.62 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound tk91) (1.95 g, 6.30 mmol) in tetrahydrofuran (20 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)-tert-butyl(1-(benzylamino)-3-(tert-butyldisulfanyl)-1-oxopropan-2-yl)carbamate (Compound tk92) (2.357 g, 5.91 mmol, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[CH3:47])[C:8](=[O:35])[C@@H:9]([NH:20][C:21](=[O:34])[C@@H:22]([N:25](C)[C:26](=O)OC(C)(C)C)[CH2:23][CH3:24])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2].[ClH:50]>O1CCOCC1.CCOCC>[ClH:50].[C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[CH3:47])[C:8](=[O:35])[C@@H:9]([NH:20][C:21](=[O:34])[C@@H:22]([NH:25][CH3:26])[CH2:23][CH3:24])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC[C@H](NC)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Yield: 85 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxobutan-2-yl(methyl)carbamate (117 mg, 170 μmol) in 4 M HCl in dioxane (848 μl) was stirred for 1 h. The reaction was diluted with Et2O and the resulting solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)butanamide hydrochloride (90.5 mg, 85%) as a white solid. MS m/z 590 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:1]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:2]2[CH:3]=[C:4]([F:16])[C:5]([C:9]([CH3:14])([CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[C:6]([F:8])[CH:7]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C(C)(C)c1c(F)cc(N)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1c(F)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
To a solution of methyl 2-(4-amino-2,6-difluorophenyl)-2-methylpropanoate (2.8 g, 12.22 mmol) and α-chloro-4-methoxytoluene (3.48 mL, 25.65 mmol) in DMF (50 mL) was added sodium hydride (60%, oil, 1.075 g, 26.87 mmol) at 0° C., and the mixture was stirred at 0° C. for 4 hr. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give methyl 2-(4-(bis(4-methoxybenzyl)amino)-2,6-difluorophenyl)-2-methylpropanoate (2.470 g, 5.26 mmol, 43.1%) as an orange oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:29][C:30](=[O:31])[N:26]([CH3:25])[C:27]4=[O:32])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CN1C(=O)CNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)nc3)CC2)c(C)c1
Yield: 36 %

Procedure:
Using (6-bromopyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 145 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (61 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][C:17]([CH3:61])([CH3:60])[CH2:18][N:19]1[CH:28]=[C:27]([S:29]([CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=[O:31])=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:45]3[CH:50]=[C:49]([C:51](=[O:56])[NH:52][CH:53]4[CH2:55][CH2:54]4)[CH:48]=[C:47]([F:57])[C:46]=3[CH3:58])[CH:25]=2)[C:20]1=[O:59])(C(C)(C)C)(C)C>C(Cl)Cl>[CH:53]1([NH:52][C:51](=[O:56])[C:49]2[CH:50]=[C:45]([C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:59])[N:19]([CH2:18][C:17]([CH3:61])([CH3:60])[CH2:16][OH:15])[CH:28]=[C:27]4[S:29]([CH:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)(=[O:31])=[O:30])[C:46]([CH3:58])=[C:47]([F:57])[CH:48]=2)[CH2:54][CH2:55]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Trifluoroacetic Acid (1 mL) was added to a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfonyl)piperidine-1-carboxylate (Example 60a, 0.116 g) in DCM (2 mL), and the reaction was stirred at room temperature for 30 min. The reaction was then azeotroped with toluene (3×10 mL), and the residue dissolved in methanol and purified by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of 0.2% aqueous NH3 in MeCN). Solvent removal and trituration with diethyl ether gave the title compound (0.026 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl.[CH3:15][N:16]1[CH2:22][C:21]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)[CH:25]=[N:26][C:20]=2[NH:19][C:18](=[O:32])[CH2:17]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]([CH3:12])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[N:26][C:20]4[NH:19][C:18](=[O:32])[CH2:17][N:16]([CH3:15])[CH2:22][C:21]=4[CH:23]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3ccc4[nH]ccc4c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a solution of (1H-indol-5-ylmethyl)methylamine (143 mg, 0.9 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (250 mg, 0.8 mmol), HOBt (121 mg, 0.9 mmol) and diisopropylethylamine (0.61 mL, 3.6 mmol) in DMF (25 mL) was added EDC hydrochloride (172 mg, 0.9 mmol). The mixture was stirred overnight at room temperature. Water (100 mL) was added and the solution was stirred for 1 hr. The precipitate was collected by filtration. The yellow solid was preabsorded onto silica gel and purified by column chromatography (95:5 CH2Cl2/MeOH) to afford (E)-N-(1H-indol-5-ylmethyl)-N-methyl-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (195 mg, 63%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 11.07 (d, J=7.6 Hz, 1H), 10.37 (m, 1H), 8.52 (dd, J=7.0, 1.9 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.59-7.26 (m, 5H), 7.07-6.92 (m, 11H), 6.38 (d, J=1.9 Hz, 1H), 4.66-4.85 (2×s, 2H), 3.74-3.77 (m, 2H), 3.42-3.38 (m, 2H), 3.08-2.90 (2×s, 3H), 2.37-2.32 (2×s, 3H); ESI MS m/z 390 [C22H23N5O2+H]+.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:25])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:11]([CH3:26])[C:10]1=[O:27])(C)(C)C.Cl>ClCCl>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:28])=[O:5])[C:10](=[O:27])[C@@H:11]2[CH3:26])=[O:25])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: C[C@H]1C(=O)N(CCC(=O)OC(C)(C)C)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 0.45 g (1.10 mmol) of 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid tert-butyl ester in 3.0 ml of dichloromethane was treated at 0° C. with 5.40 ml (21.60 mmol, 4 M in dioxane) of HCl and stirred and warmed up to RT over night. The reaction was evaporated, dissolved in toluene and evaporated (3×) to give 0.52 g (quant.) of the titled compound as light yellow foam. MS: 372.1 (M−H−, 2Cl).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:3]1[CH3:18].[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:18])=[C:4]2[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH3:24])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2ccncc2)c2cc(O)ccc2n1C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 1,2-dimethyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([O:13][CH3:14])=[O:12])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.C(SC1C(C(OC)=O)=C(C(F)(F)F)C=C(SCC)N=1)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CC#N.O.CCOC(C)=O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([O:13][CH3:14])=[O:12])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=[C:2]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[N:7]=1)[CH3:10]
Reactant: C1COCCN1
Reactant: CCSc1nc(Cl)cc(C(F)(F)F)c1C(=O)OC
Agent: CCSc1cc(C(F)(F)F)c(C(=O)OC)c(SCC)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)OC
Temperature: 150 °C
Yield: 16 %

Procedure:
A solution of 2 g of a ˜1:1 mixture of methyl 6-chloro-2-(ethylsulfanyl)-4-(trifluoromethyl)-pyridine-3-carboxylate and methyl 2,6-bis(ethylsulfanyl)-4-(trifluoromethyl)-pyridine-3-carboxylate, 1.7 ml (20.0 mmol) morpholine and 3.5 ml (20.0 mmol) DIPEA in MeCN (10 ml) was heated in the microwave to 150° C. for 4 h. The RM was then diluted with water and EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 440 mg (1.3 mmol, 16% over 2 steps) methyl 2-(ethylsulfanyl)-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:19]=1.C(Cl)(Cl)Cl>C1COCC1.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]>[N:1]1([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([Si:27]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:36])[CH3:35])[CH:28]([CH3:29])[CH3:30])[CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2ccccc21
Reactant: C1CCNCC1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCCCC2)c2ccccc21
Temperature: 70 °C
Yield: 27.2 %

Procedure:
Dissolve piperidine (1.28 mL, 12.9 mmol) in THF (10 mL) and treat with lithium bis(trimethylsilyl)-amide (1.0M in THF, 11.2 mL, 11.2 mmol). To the above solution add 3-bromo-1-triisopropylsilanyl-1H-indole (TCI-US, 3.04 g, 8.62 mmol), (2′-dicyclohexyl-phosphanyl-biphenyl-2-yl)-dimethyl-amine (88 mg, 0.22 mmol), and Pd2dba3.CHCl3 (225 mg, 0.22 mmol). Heat the red solution to 70° C. for 4 h then cool to RT and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 40% EtOAc/hexanes, to give the title compound (837 mg, 27%). MS (ES+) 357.2 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, 1H, J=8.4), 7.41 (d, 1H, J=8.4), 7.07 (m, 2H), 6.68 (s, 1H), 3.03 (m, 4H), 1.79 (m, 4H), 1.65 (septet, 3H, J=7.7), 1.58 (m, 2H), 1.12 (d, 18H, J=7.1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[F:19][CH:20]([F:24])[C:21](Cl)=[O:22]>O1CCOCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[CH:20]([F:24])[F:19])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Reactant: O=C(Cl)C(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(Cl)ccc1NC(=O)C(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 1 g of 2-amino-5-chlorobenzenesulphonamide (obtained in accordance with J. Chem. Soc. Perkin I 1979, 1043-1047) dissolved in 4 ml of dioxane there are added, in the cold state (+5° C.), 0.6 ml of pyridine and 0.6 ml of difluoroacetic acid chloride. The flask is hermetically closed immediately and subjected to vigorous stirring at ambient temperature for 10 minutes. The solvents are then removed under reduced pressure. The solid residue is taken up in water (12 ml), and the insoluble material is collected by filtration, washed with water and dried to yield the expected compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[C:9](=[O:16])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:3][CH2:2]1.[CH2:26]([NH2:28])[CH3:27].Cl.CCN(C(C)C)C(C)C>>[CH2:26]([NH:28][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([CH:8]([C:9](=[O:16])[NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:18][CH:19]=1)[CH3:27]
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1
Reactant: CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1

Procedure:
4-[2-(Tetrahydropyran-4-yl)-1-(thiazol-2-ylcarbamoyl)ethyl]benzoic acid (Preparation 62, 150 mg, 420 μmol) was condensed with EtNH2.HCl in the presence of DIPEA, utilising the general procedure described in EXAMPLE 65, to give the title compound: RTA=2.97 min; m/z (ES+)=388.3 [M+H]+.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1>>[Cl:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2([CH2:5][OH:16])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc(F)c(Cl)cc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(F)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4-chloro-5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (50% for two steps): MS (ES+) m/z 360 (M−17), 400 (M+23).
Reaction SMILES: [CH2:1]([N:4]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16](O)[C:15]2=[O:20])=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[NH:57][CH2:56][CH2:55][CH2:54]2>C(Cl)Cl>[CH2:1]([N:4]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][C@H:16]([N:57]3[C:58]4[C:53](=[CH:52][C:51]([Cl:50])=[CH:60][CH:59]=4)[CH2:54][CH2:55][CH2:56]3)[C:15]2=[O:20])=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O)C2=O)nc1
Reactant: Clc1ccc2c(c1)CCCN2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@H](N3CCCc4cc(Cl)ccc43)C2=O)nc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
Prepared using General Procedure 4, Method A. To a stirring solution of (R)-N-allyl-6-(3-hydroxyl-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide (75 mg, 0.20 mmol) in DCM (0.6 mL), under N2, was added diisopropylethylamine (70 μL, 0.40 mmol). The solution was then cooled to −40° C. in a dry ice/acetone bath and triflic anhydride was added (37 μL, 0.22 mmol). The reaction was stirred at −40° C. for 30 minutes then a solution of 6-chloro-1,2,3,4-tetrahydroquinoline (50 mg, 0.30 mmol) dissolved in DCM (0.3 mL) was added. The solution was allowed to warm to −20° C. and was placed in the −20° C. freezer overnight. The solution was then allowed to warm to room temperature and was washed with saturated aqueous NaHCO3 (5 mL), and the aqueous layer extracted once with DCM (5 mL). The organic layers were combined and concentrated. The residue was purified by silica gel chromatography with 5%-70% EtOAc in hexanes to give (S)-N-allyl-6-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide (94 mg) in 89% yield. LC/MS (10%-99% CH3CN/H2O (0.05% TFA)), m/z: M+1 obs=530.1, tR=2.05 min.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4]C=1.C(C1C=C2C(=CC=1)[NH:33]C(=O)/C/2=C\C1NC=CC=1)#C.BrC1C=NC=CC=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[N:33]1[CH:2]=[CH:7][CH:6]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Brc1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3cccnc3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (47 mg, 0.21 mmol) (Example 82) was coupled with 3-bromopyridine (33 mg, 0.30 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (15 mg, 0.021 mmol) (Aldrich) as catalyst in 1 mL DMF and I mL triethylamine at 70° C. for 15 hours to give (Z)-1,3-dihydro-5-(3-pyridinyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 30 mg, 47%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:6][CH2:7][CH3:8].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:19][N:18]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8]
Reactant: CCCN(CCCN)c1ccccn1
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Product: CCCN(CCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-propylamino]pyridine (1.16 g) and 2-methylthio-5-(4-fluorobenzyl)pyrimid-4-one (1.25 g) were fused together on an oil bath at 160° C. for 5 hr. On cooling the residue was crystallised twice from ethanol and finally from ethanol/water to give 2-[3-(N-propyl-N-pyrid-2-ylamino) propylamino]-5-(4-fluorobenzyl)pyrimid-4-one 1.2H2O, 0.75 g (36%) mp 107°-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.N#N.[Si]([C:17]#[N:18])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:17]#[N:18])=[C:4]([Cl:10])[CH:3]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CC#N
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
4-Bromo-1-bromomethyl-2-chloro-benzene (3.04 g, 10.7 mmoles) was dissolved into anhydrous CH3CN. To this mixture (under N2 at ambient temp) was added TMSCN (2.1 mL, 15.7 mmoles) followed by 1.0M TBAF (15.7 mL, 15.7 mmoles, soln in THF). The resulting mixture was stirred at ambient temperature for 15 min after which time it was evaporated in vacuo to yield crude residue. The crude residue was purified using flash silica chromatography (0-10% EtOAc/Hexane) to yield (4-bromo-2-chloro-phenyl)-acetonitrile (1.98 g, 80%) as an off-white solid. 1H-NMR (CDCl3): δ 7.60 (d, J=2.0 Hz, 1H), 7.47 (dd, J′=8.1 Hz, J″=1.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.79 (s, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][C:12](=[O:14])[C:11]([C:15](O)=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([O:19][C:20](=[O:22])[CH3:21])=[CH:7][C:8]2[S:13][C:12](=[O:14])[C:11]([C:15]([Cl:25])=[O:16])=[CH:10][C:9]=2[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)sc2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)sc2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-2-oxo-2H-1-benzothiopyran-3-carboxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in benzene (15 mL), and then the solvent was distilled off. Benzene (15 mL) was added to the residue, and the benzene was distilled off again, followed by vacuum drying to yield 6,7-diacetoxy-2-oxo-2H-1-benzothiopyran-3-carbonyl chloride.