Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20](O)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH2:49]>CN(C=O)C.ClCCl>[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH:49][C:20](=[O:21])[C@@H:19]1[CH2:23][CH2:24][CH2:25][N:18]1[C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)CN
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
To a solution of N-Cbz-valylproline (Cbz-NH-[VP]-CO2H) (3.5 g, 10 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (1.6 g, 11 mmol) and triethylamine (2.0 g, 20 mmol) in DMF (15 mL) is added dropwise a solution of glycine methyl ester hydrochloride (1.38 g, 11 mmol) in DMF (5 mL). The solution is stirred at room temperature and the reaction monitored by TLC until the disappearance of N-Cbz-valylproline. The reaction solution is then diluted with dichloromethane (50 mL) and the organic layer is extracted with 0.1 N HCl (20 mL), water (20 mL), then dried over Na2SO4. The solvent is removed in vacuo to afford the desired compound.
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.CO.COCCOCCO.S(=O)(=O)(O)O>[Zn].O>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: COCCOCCO
Solvent: CO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C

Procedure:
50 Parts of 1-hydroxylaminoanthraquinone was stirred into a mixture of 700 parts of diethyleneglycol monomethyl ether, 100 parts of water and 30 parts of conc. sulfuric acid, then added thereto little by little 16 parts of zinc dust over 1 hour after heating to 80°C. The reaction mixture was maintained at 80°C for additional 2 hours and then filtered. The filtrate was washed with water and dried to obtain 43.5 parts of 1-aminoanthraquinone of a purity of 94 %.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[O:38]1[CH2:42][CH2:41][CH:40]([C:43](=[S:45])[NH2:44])[CH2:39]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:45][C:43]([CH:40]3[CH2:41][CH2:42][O:38][CH2:39]3)=[N:44][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)C1CCOC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1.00 g, 2.26 mmol), NBS (0.423 g, 2.38 mmol) and tetrahydro-3-furancarbothioamide (0.386 g, 2.94 mmol) the title compound of Step D was obtained as an orange solid (890 mg, 1.42 mmol, 62.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 7.59-7.83 (m, 1H), 7.40-7.55 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.87 (d, J=5.3 Hz, 1H), 3.98-4.09 (m, 1H), 3.71-3.99 (m, 4H), 2.35-2.48 (m, 1H), 2.09-2.28 (m, 1H). MS (ESI) 553.03 [M+H]+.
Reaction SMILES: C([O-:3])C.[Na+].[CH2:5]([O:7][C:8](=[O:11])[CH2:9][SH:10])[CH3:6].[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([N:17]=[C:18]([O:25]C)[C:19](OC)=[N:20]2)=[C:15]([CH2:27]Br)[CH:14]=1.Cl>C(O)C.O1CCCC1>[CH2:5]([O:7][C:8](=[O:11])[C:9]([S:10][CH2:27][C:15]1[CH:14]=[C:13]([Br:12])[CH:22]=[C:21]2[C:16]=1[NH:17][C:18](=[O:25])[CH2:19][NH:20]2)=[O:3])[CH3:6]
Reactant: CC[O-]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Reactant: CCOC(=O)CS
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)SCc1cc(Br)cc2c1NC(=O)CN2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.5 ml (4 mmol) of a 21% solution of sodium ethanolate in ethanol are diluted with 10 ml of ethanol under nitrogen. 601 mg (5 mmol) of thioglycolic acid ethyl ester are added at 0° C. and the mixture is heated to 20° C. After one hour, 1.09 g (3 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline, 10 ml of ethanol and 10 ml of tetrahydrofuran are added. The mixture is stirred for 18 hours, acidified with 2 ml of 2N hydrochloric acid and concentrated by evaporation. The residue is extracted with ethyl acetate and 0.1N hydrochloric acid, and the combined organic phases are washed with 10% sodium carbonate solution and brine, dried over magnesium sulfate and concentrated by evaporation. The residue is dissolved in 20 ml of a 33% solution of hydrogen bromide in acetic acid, and the solution is heated at 130° C. for 20 minutes and cooled to approximately 80° C. 20 ml of ethanol are added with stirring and the solution is left to stand at 5° C. for 18 hours. The crystals are filtered off, washed with cold ethanol and dried.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:1][N:2]2[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:15])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CC(C)c1nn(N)c(=O)c2ccccc12
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1nn(NC(=O)Cc2cc(F)cc(F)c2)c(=O)c2ccccc12
Reaction time: 8 h
Yield: 32.4 %

Procedure:
A mixture of the product of Example 1B (44.5 mg, 0.219 mmol), triethylamine (0.050 mL, 0.36 mmol), 2-(3,5-difluorophenyl)acetic acid (41.0 mg, 0.238 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (77.5 mg, 0.241 mmol) in DMF (0.75 mL) was stirred overnight, diluted with EtOAc, washed with 1 N NaOH and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (8% EtOAc/CH2Cl2) to give the title compound as a white solid (25.4 mg, 0.071 mmol). 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.33 (dd, 1H), 8.16-8.09 (m, 1H), 8.00 (td, 1H), 7.89 (ddd, 1H), 7.19-7.07 (m, 3H), 3.75 (s, 2H), 3.61 (quin, 1H), 1.27 (d, 6H); MS (ESI+) M/Z 357.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][N:9]=[C:10]([C:12]2[O:16][C:15]([N:17]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:18][C:19]([O:21]CC)=[O:20])=[N:14][CH:13]=2)[CH3:11])=[CH:5][CH:4]=1.CO.O.[OH-].[Li+]>C1COCC1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][N:9]=[C:10]([C:12]2[O:16][C:15]([N:17]([CH2:24][C:25]([OH:27])=[O:26])[CH2:18][C:19]([OH:21])=[O:20])=[N:14][CH:13]=2)[CH3:11])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)c1ncc(C(C)=NOCc2ccc(C(F)(F)F)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=NOCc1ccc(C(F)(F)F)cc1)c1cnc(N(CC(=O)O)CC(=O)O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of the product of step 3 (295 mg, 0.62 mmoles) in a mixture of THF (6 ml), methanol (2 ml) and water (2 ml), lithium hydroxide (105 mg, 1.25 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with 1N HCl. White solid seperated was filtered and washed with water & dried over P2O5 under vacuum to give 250 mg (82%) of title product as off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2.[NH2:17][C:18]1[C:19]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]2)=[C:20]2[CH2:26][CH2:25][O:24][C:21]2=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]([NH:17][C:18]2[C:19]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]3)=[C:20]3[CH2:26][CH2:25][O:24][C:21]3=[N:22][CH:23]=2)=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reactant: CCc1ccc2cc(N)c(C(=O)O)nc2c1
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: CN(C)C=O
Product: CCc1ccc2cc(N)c(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCO4)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.7 %

Procedure:
3-Amino-7-ethylquinoline-2-carboxylic acid (24.5 mg, 0.113 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (38.3 mg, 0.114 mmol) and HATU (136.1 mg, 0.3579 mmol), DMF (2.00 mL) was added, followed by DIPEA (152.9 mg, 1.183 mmol). The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. To the resulting residue DCM (2.0 mL) was added followed by T (2.0 mL). The mixture was stirred at room temperature for 30 min. and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a yellow solid (5.7 mg, 12%). LCMS calc. for C24H29N6O2 (M+H)+: m/z=433.2. found 433.2. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.65-7.61 (m, 2H), 7.51 (s, 1H), 7.37 (dd, J=8.6, 1.5 Hz, 1H), 6.81 (s, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.46-3.39 (m, 2H), 3.22-3.17 (m, 1H), 3.17-3.10 (m, 1H), 3.07-3.00 (m, 1H), 2.88-2.81 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 2.67-2.59 (m, 1H), 2.00-1.92 (m, 1H), 1.92-1.79 (m, 2H), 1.28 (t, J=7.5 Hz, 3H), 1.26-1.20 (m, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1Br

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (21.5 g, 100 mmol) in 500 mL of methanol and 8 mL of concentrated sulfuric acid is refluxed overnight. Methanol is removed under reduced pressure, the residue is taken up in ether, washed with sodium bicarbonate, brine, and dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give methyl 2-bromo-3-methylbenzoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][CH:56]([OH:59])[CH2:55][CH2:54]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:59][CH:56]1[CH2:57][CH2:58][N:53]([CH2:52][CH2:51][NH:50][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:54][CH2:55]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCCN1CCC(O)CC1
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: O=C(O)C(F)(F)F
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), DIPEA (115 mg, 5 eq.) and 1-(2-amino-ethyl)-piperidin-4-ol TFA salt (88 mg, 1.2 eq.) in 2 mL) was stirred at rt for 45 mins. To the mixture was added HATU (83 mg, 1.1 eq.). After stirring for 18 hours, the reaction was concentrated and purified on a silica gel column to give the titled compound as a yellow solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[C@:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=[O:7])(C)(C)C.[CH2:31]([O:38][CH2:39][CH:40]([NH:44][C:45](=[O:57])[C:46]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])([CH3:48])[CH3:47])C(O)=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[C:53]([O:52][C:50](=[O:51])[NH:49][C:46]([C:45](=[O:57])[NH:44][C@H:40]([CH2:39][O:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:16](=[O:17])[C@:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=[O:7])([CH3:48])[CH3:47])([CH3:54])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(COCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1

Procedure:
reacting said 1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester with 3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionic acid in the presence of a tertiary amine and 1-propanephosphonic acid cyclic anhydride in a reaction inert solvent to form (1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester; and
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24](=[O:27])[C:23]2=[O:28]>O1CCCC1>[OH:28][C:23]1([C:7]2[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=2)[C:22]2[C:26](=[C:18]([C:17]([F:16])([F:29])[F:30])[CH:19]=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:27]
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1=O
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1Nc2c(C(F)(F)F)cccc2C1(O)c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 175 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (9.63 g, 69.7 mmol) in anhydrous tetrahydrofuran (200 mL) was added dropwise a solution of isopropyl magnesium chloride (92.9 mmol, 46.5 mL, 2.0 M solution in tetrahydrofuran) over 30 min at 0° C. 7-Trifluoromethylisatin (4.00 g, 22.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 4 h and the reaction was quenched by the addition of 10% aqueous hydrochloric acid (25.0 mL) and the mixture was concentrated in vacuo to dryness. The residue was diluted with ethyl acetate (200 mL), washed with saturated ammonium chloride (3×30.0 mL), brine (3×30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with hot diethyl ether to afford 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (13.6 g, 83%): 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.21 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 6.95 (dd, J=7.7, 7.7 Hz, 1H), 6.57 (s, 1H), 6.17 (s, 1H), 5.89 (d, J=6.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 179.2, 148.6, 147.3, 141.0, 139.9, 135.7, 127.9, 125.3, 124.3, 121.7, 119.8, 110.1, 107.2, 101.2, 97.7, 73.9; MS (ES−) m/z 352.2 (M−1).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:25][NH2:26].C(O)C>>[ClH:1].[F:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]\[CH2:2][NH:26][CH3:25])[S:7]1(=[O:24])=[O:23]
Reactant: Cc1ccc(N2c3ccccc3N(C/C=C\CCl)S2(=O)=O)c(F)c1
Reactant: CN
Solvent: CCO
Product: CNC/C=C\CN1c2ccccc2N(c2ccc(C)cc2F)S1(=O)=O
Product: Cl

Procedure:
A solution of 1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.1 g) was stirred in an 8 M methylamine-ethanol solution at 22° C. for 16 h. The reaction mixture was concentrated under reduced pressure to provide (2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbut-2-en-1-amine hydrochloride (0.12 g) as a white solid:
Reaction SMILES: [CH3:1][Si:2]([Cl:5])(Cl)[Cl:3].C(OCC)C.Cl[Mg][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15]>CCCCCC>[CH3:13][Si:14]([CH2:17][Si:2]([CH3:1])([Cl:5])[Cl:3])([CH3:16])[CH3:15]
Reactant: C[Si](Cl)(Cl)Cl
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)C[Si](C)(Cl)Cl
Reaction time: 2 h
Yield: 43 %

Procedure:
In a 1-1 flask equipped with a dropping funnel, reflux condenser, stirrer and nitrogen gas introducing tube were placed 149 g (1 mol) of methyltrichlorosilane and 250 ml of diethyl ether. While stirring the mixture, the above chlorotrimethylsilylmethyl magnesium was dropwise added thereto over a period of 2 hours. After completion of the addition, the mixture was refluxed with heating and stirring for 36 hours. After cooling, 200 ml of hexane was added to the reaction mixture, and the salts formed were filtered off. The filtrate was condensed and vaccum-distilled. 11.7 g (yield: 43%) of (trimethylsilylmethyl)methyldichlorosilane was obtained.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:28]([O-])=O)[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC(O)=O.O>CCOC(C)=O.[Fe]>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 112.7 %

Procedure:
A mixture of 4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (64 mg, 0.15 mmol), AcOH (0.90 mL), water (0.10 mL) and iron powder (149 mg, 2.66 mmol) was stirred at room temperature for 20 min. The mixture was diluted with EtOAc and filtered through a short silica gel plug. The filtrate was concentrated under reduced pressure, diluted with EtOAc and washed with aq. Na2CO3. The organic layer was dried, filtered and concentrated under reduced pressure to give the sub-title compound (66 mg) as a yellowish solid, which was used without further purification. LCMS calc. for C20H31N4O4 (M+H)+: m/z=391.2. Found: 391.1.
Reaction SMILES: [Li+].[OH-:2].C1[CH2:7][O:6]CC1.O.C(OC([C:14]1[N:15]=[C:16]([NH:19][C:20](=[O:46])[C@@H:21]([NH:29][C:30](=[O:45])/[CH:31]=[CH:32]/[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[N:40]2[CH:44]=[N:43][N:42]=[N:41]2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17][CH:18]=1)=O)C.ClCl>>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([N:40]2[CH:44]=[N:43][N:42]=[N:41]2)=[C:33](/[CH:32]=[CH:31]/[C:30]([NH:29][C@@H:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([NH:19][C:16]2[S:17][C:18]([C:7]([OH:6])=[O:2])=[CH:14][N:15]=2)=[O:46])=[O:45])[CH:38]=1
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: CCOC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)n1
Agent: ClCl
Agent: [Li+]
Solvent: O
Product: O=C(/C=C/c1cc(Cl)ccc1-n1cnnn1)N[C@@H](Cc1ccccc1)C(=O)Nc1ncc(C(=O)O)s1

Procedure:
LiOH/THF/water hydrolysis of 2-{(S)-2-[(E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acryloylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid ethyl ester (Example 18) afforded Example 22. HPLC purity: >97%. LCMS m/z 524.3 (M+H, chlorine isotope). 1H NMR (400 MHz, CD3OD) δ: 9.49 (s, 1H), 7.96 (ds, 2H), 7.72-7.54 (m, 2H), 7.27 (m, 5H), 7.10 (d, J=15.7 Hz, 1H), 6.75 (d, J=15.7 Hz, 1H), 4.90 (m, 1H), 3.27 (m, 1H), 3.11 (m, 1H) ppm. Analytical HPLC RT: 5.58 min (Method C, 8 min gradient).
Reaction SMILES: [ClH:1].[CH2:2]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)[CH2:3][CH3:4].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:1].[CH2:26]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)[CH2:2][CH2:3][CH3:4])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCBr
Reactant: CCCNCCc1ccc(OC)c(OCCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(CCC)CCc1ccc(OC)c(OCCc2ccccc2)c1

Procedure:
432 mg of N-n-propyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride, 0.87 ml of 1-bromo-n-hexane and 379 mg of anhydrous potassium carbonate were stirred in 4.4 ml of N,N-dimethylformamide at room temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by evaporation of the solvent under reduced pressure. The residue was subjected to silica gel chromatography (developing solvent; n-hexane:ethyl acetate=1:1). The target fraction was concentrated and dissolved in 2 ml of ethyl acetate. After adding 0.25 ml of a 4N solution of hydrogen chloride in ethyl acetate, the solvent was evaporated to give 358 mg of oily N-n-hexyl-N-n-propyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(O)cc2)cc1
Yield: 24.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.017 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide as a white solid.