Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[CH3:13][O:14][C:15](=[O:20])C[C@H](O)C.CO[C:23](=[O:28])[C:24]([O:26]C)=[O:25].Cl>CCCCCC.O1CCCC1.C(OCC)(=O)C>[OH:28][C:23]1[C:24]([O:26][C@H:10]([CH3:11])[C:12]=1[C:15]([O:14][CH3:13])=[O:20])=[O:25]
Reactant: COC(=O)C[C@@H](C)O
Reactant: COC(=O)C(=O)OC
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C1=C(O)C(=O)O[C@@H]1C
Temperature: 0 °C

Procedure:
775 ml of 1.6M n-butyllithium solution in n-hexane are added dropwise within a period of 20 minutes at -25° C. to a solution of 1.27 mol of diisopropylamine in 600 ml of tetrahydrofuran. At -70° C., 70.9 g of (R)-3-hydroxybutyric acid methyl ester are then added dropwise within a period of 30 minutes and, after 1 hour, 70.9 g of oxalic acid dimethyl ester are added dropwise within a period of 40 minutes. After a reaction time of two hours at -60° C., the whole is warmed to 0° C. and acidified to pH 2 with 430 ml of 6N hydrochloric acid. The product is isolated by repeated extraction with ethyl acetate and pre-purified by extraction into aqueous bicarbonate solution, acidification with 6N hydrochloric acid to pH 2.5 and extraction once more with ethyl acetate. The solvent is distilled off and the residue is recrystallised from ether/petroleum ether. [α]D20 =+30.0° (3% in CHCl3), m.p. 94°-96° C.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1I.C([Li])CCC.CN(C)[CH:17]=[O:18]>C(OCC)C>[Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Cc1c(I)sc(I)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(I)sc(C=O)c1Br
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
A suspension of 3-bromo-2,5-diiodo-4-methylthiophene (43 g, 100 mmol) in diethyl ether (300 mL) was treated with an etheral solution of 2.5 M butyllithium (40 mL, 100 mmol) during 5 min at −70 to −60° C. After 10 min, the mixture was treated with N,N-dimethylformamide (11 mL, 140 mmol) and the cooling bath was removed. Upon warming to 23° C., the mixture was quenched with 10% aqueous NH4Cl (500 mL) and extracted with ethyl acetate (3×500 mL). The combined extracts were washed with water and brine (500 mL each), dried (MgSO4) and concentrated in vacuo to give the crude product (31 g) as a rust-colored solid which was recrystallized from hot ethyl acetate. Vacuum filtration gave the title compound (25 g, 76%, m.p. 152-53° C.) as rust-colored needles.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]#[N:12])=[CH:5][CH:4]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26]>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][C:11]1[CH:10]=[C:9]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[N:12]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=2)[N:12]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: NCc1ccco1
Reactant: COc1ccc(C=CC#N)cc1
Product: Cc1cc(Nc2cc(NCc3ccco3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 162 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials 3-(4-methoxyphenyl)acrylonitrile, 5-methyl-1H-pyrazole-3-amine, and (furan-2-yl)methanamine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Product: CS(=O)(=O)c1ccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)cc1
Yield: 12 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 4-(methylsulfonyl)phenylhydrazine according to the method described for Example 1 in 12% yield. MS: M=392.9 (M+H)+
Reaction SMILES: [Na].[CH2:2](O)C.[CH:5]1[C:18]2[CH:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.CI>O>[CH:15]1[C:16]2[CH:17]([C:19]([O:21][CH3:2])=[O:20])[C:18]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCO
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Agent: [Na]
Solvent: CI
Solvent: O
Product: COC(=O)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sodium ethoxide solution is prepared from 21.75 g (0.95 mol) of sodium and 1500 mL of ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid is added batchwise to this solution and the suspension obtained is stirred for 1 hour at ambient temperature. Then the solid is separated off, washed with 1500 mL diethyl ether, and the isolated crystals are suspended in 1500 mL of dimethylformamide and combined with 126.73 mL (2.0 mol) of methyl iodide with stirring. The solution formed is left to stand for 24 hours at ambient temperature, then diluted with water to a total volume of 6 L, crystallized, suction filtered, washed with water, and dried. Yield: 167 g of white crystals (74% of theoretical yield); melting point: 82° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:19]=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18].N#N.[H][H].[H][H]>[Ni]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:2]=2[Cl:1])=[C:10]([F:18])[CH:11]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Agent: [Ni]
Agent: N#N
Product: Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
To a reactor was added 10 g of 3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine, 1.4 g of Ra-Nickel (type A-5001 from Johnson Matthay) and 100 mL of Me-THF. The reactor was inerted by three nitrogen/hydrogen swings, then pressurized to 25 psig with hydrogen. The reaction mixture was stirred under 25 psig of hydrogen at 25° C. until the hydrogen uptake ceased (1.6 L consumed) and the reaction was judged complete by HPLC. BuOAc (50 mL) was added to the reaction mixture and MeTHF was distilled off under atmospheric pressure until <1% of Me-THF were detected by GC. Maintaining a batch temperature of 90° C., heptane (50 mL) was added over 20 min. The solution was then allowed to cool to room temperature over 8 hrs. The solids were filtered off and the cake was washed with 50 mL heptane. The solid was dried in a vacuum oven at 60° C. for 12 hr to afford 4-(4-Amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (8.88 g; 95% yield) as a light yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:15])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:6][C:5]([F:16])=[C:4]([Cl:17])[N:3]=1.[C:18](O)(=O)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[Cl:17][C:4]1[N:3]=[C:2]2[C:7]([C:8](=[O:15])[C:9]([C:10]([OH:12])=[O:11])=[CH:18][N:25]2[CH:22]2[CH2:24][CH2:23]2)=[CH:6][C:5]=1[F:16]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: NC1CC1
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 358.8 %

Procedure:
To a stirred solution of 3-(2,6-Dichloro-5-fluoropyridin-3-yl)-3 -oxo-propanoic acid ethyl ester (compound (1): 85.0 kg, 303 mol) in toluene (808 kg)was added Me2 NCH(OMe)2 (40.8 kg ) and acetic acid (4.56 kg). The mixture was stirred at room temperature for 50 minutes. Cyclopropylamine (22.53 kg) was added to the reaction mixture, and the mixture was stirred at 25 to 35° C. for 50 minutes. The reaction mixture was washed with 10% aqueous citric acid solution, and then water. After layer separation, the aqueous layer was discarded, and tetrabutylammonium bromide (4.88 kg) and 25% aqueous sodium hydroxide solution (53 kg) were added to the separated organic layer. The resulting mixture was stirred for 2 hours. 35% aqueous hydrochloric acid solution (142 kg) was added, and the resulting mixture was heated at reflux. After about 8 hours, the reaction mixture was cooled, and water (about 50 kg) was added thereto, and then the aqueous layer was separated off. The reaction solution was washed with water, and the solid compound present in the separated organic layer was filtered, and washed with isopropanol, water, and isopropanol in sequence. The resulting solid was dried under vacuum to give the title compound (77 kg) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].CNC=[O:29].CO>C(O)(C)C>[CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].[CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].[OH2:29]
Reactant: CNC=O
Agent: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccc(O)cc3)[C@H]2SC1
Solvent: CO
Solvent: CC(C)O
Product: O
Temperature: 10 °C

Procedure:
Cefadroxil monomethylformamide solvate (30 g) prepared according to Example 3 was slurried in 150 ml of a mixture 1:1 of methanol and isopropyl alcohol at 52° C. After 70' at 52° C. the mixture was cooled to 10° C., filtered and washed with acetone to yield 23.2 g of crystalline cefadroxil hemihydrate.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]#[N:15])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:26]>CO>[F:17][C:2]([F:1])([F:16])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:26])[NH2:15])=[N:6]1
Reactant: N#Cc1nn(CCC(F)(F)F)c2ncccc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(CCC(F)(F)F)c2ncccc12
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To the intermediate from Step A above (44.4 g, 185 mmol) in MeOH (16 mL) at rt was added sodium methoxide (13.98 g, 259 mmol). After stirring for 3 hours, acetic acid (42.3 mL, 739 mmol) and ammonium chloride (12.85 g, 240 mmol) were added to the reaction. The resulting slurry was heated to 65° C. and stirred for 4 hours. The reaction was then cooled to rt and quenched with EtOAc and saturated aqueous NaHCO3. The aqueous layer was removed and back extracted with EtOAc (4×). The combined organic layers were washed with 20% brine and dried over Na2SO4, filtered and the solvent removed under vacuum. EtOAc was added and the precipitated product was filtered and washed with methyl tert-butyl ether. The solid was dried at rt under vacuum oven overnight and the material used without further purification. 1H NMR (500 MHz, CH3OH-d4): δ 8.74 (d, J=4.57 Hz, 1H); 8.52 (d, J=8.32 Hz, 1H); 7.51 (dd, J=8.31, 4.44 Hz, 1H); 4.96 (t, J=6.91 Hz, 3H); 3.08-2.97 (m, 2H). m/z=258.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[N:20]([CH3:32])[C:21](=[O:31])[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:23][C:13]3=2)[NH:8][N:9]=1)[CH3:2].[CH3:33]I>>[CH2:1]([O:3][CH2:4][C:5]1[N:9]([CH3:33])[N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[N:20]([CH3:32])[C:21](=[O:31])[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[CH:23][C:13]3=2)[CH:6]=1)[CH3:2]
Reactant: CI
Reactant: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)[nH]n1
Agent: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n[nH]1
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, with the compound from Example 117, 6-(5-ethoxymethyl-1H-pyrazol-3-yl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and methyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:18])=O>CN(C=O)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC

Procedure:
An analogous reaction to that described in Example 1, starting with 6,7-Dimethoxy-3H-quinazolin-4-one (31) reacted with thionylchloride in presence of DMF gave compound 32.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].[C:13]([O-])(=O)[CH3:14].[Na+].C(O)(=O)C>O>[CH2:7]([CH:1]1[CH2:6][CH2:5][C:4]2[CH:3]([CH2:9][CH2:8][C:10](=[O:11])[CH:12]=2)[CH2:2]1)[CH2:13][CH3:14]
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1
Reactant: C=CC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC1CCC2=CC(=O)CCC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
212 g of 4-propylcyclohexanone and 200 ml of pyrrolidine was dissolved in 600 ml of toluene, and the mixture was heated with stirring for 3 hours, and any azeotropically distilled water was removed. Excess pyrrolidine was then removed by azeotropic distillation with toluene, to obtain 1-(4-propylcyclohexa-1-en-1-yl)-pyrrolidine. The crude product was cooled, as is, to room temperature, a further 800 ml of toluene was added, the mixture was cooled in a water bath, and 120 ml of methyl vinyl ketone was added dropwise over a period of 1 hour at a temperature of 25° C. or lower. Following completion of the addition, the mixture was immediately heated and refluxed for 20 hours. The solution was then cooled to room temperature, a buffer solution of pH 5 prepared from 63 g of sodium acetate, 120 ml of acetic acid and 140 ml of water was added, and the reflux was continued for a further 4 hours. After the solution had been cooled to room temperature, the organic layer was separated and washed with water and a saturated aqueous solution of sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, and the solvent removed by evaporation to obtain 320 g of a crude product of 6-propyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.N1CCC[C@@H]1C[OH:28].CC[N:34]([CH:38]([CH3:40])C)[CH:35]([CH3:37])C>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:34]5[CH2:35][CH2:37][C@@H:40]([OH:28])[CH2:38]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC[C@@H](O)C3)cc1OCC2
Yield: 34 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and (R)-prolinol hydrochloride with added DIPEA (2.2 eq.), were reacted and the crude product recrystallised from methanol to give 371 as a green solid (46 mg, 34%). LCMS: RT=2.26 min, [M+H]+=382. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1 H, s), 7.88 (1 H, d, J=0.63 Hz), 7.82 (1 H, s), 5.97-5.96 (1 H, m), 5.94 (1 H, s), 4.97 (1 H, d, J=3.62 Hz), 4.49-4.48 (4 H, m), 4.39 (1 H, s), 3.53-3.42 (3 H, m), 2.02-2.00 (1 H, m), 1.90-1.87 (1H, m), 1.48 (6 H, d, J=6.60 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[CH:19]=2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH3:26][O:25][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:15]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2cc(Br)cnc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3c2)cc1

Procedure:
Followed Step 1 of Compound IV-1, starting from 4-(methoxycarbonyl)phenylboronic acid and Intermediate 13, and where the base used was Na2CO3, the solvent DME/H2O (8:2), and the reaction was run at 100° C. for 2 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]=1[CH:27]=O)=[O:8].[CH3:33][NH:34][CH3:35].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]=1[CH2:27][N:34]([CH3:35])[CH3:33])=[O:8]
Reactant: CNC
Reactant: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C=O)n(Cc3ccccn3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(CN(C)C)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General Procedure P. To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 94, 70 mg, 0.16 mmol) in ClCH2CH2Cl (10 ml) at room temperature was added dimethylamine (2 M in THF, 0.24 ml, 0.48 mmol), HOAc (14 μl, 0.24 mmol), and NaBH(OAc)3 (102 mg, 0.48 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc, then 9:1 EtOAc-Et3N, then 7:2:1 CH2Cl2-MeOH-Et3N) to yield the title compound as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][S:10]1)(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>C(Cl)Cl>[S:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][NH2:7].[F:15][C:16]([F:21])([F:20])[C:17]([O-:19])=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC1CCCS1
Solvent: ClCCl
Product: NCC1CCCS1
Product: O=C([O-])C(F)(F)F
Yield: 83 %

Procedure:
A solution of 2-[(N-tbutoxycarbonlylamino)methyl]-tetrahydrothiophene 222 (500 mg, 2.3 mmol) in DCM (25 mL) was treated with trifluoroacetic acid (10 mL). The mixture was stirred at rt for 1 h before the DCM and excess TFA were removed under reduced pressure. The oily residue was triturated with diethyl ether to afford 223 as its trifluoroacetate salt (440 mg, 1.9 mmol, 83%) as an off-white solid, which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18](O)=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18]([NH:41][CH:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:39]([O:38][CH3:37])=[O:46])=[O:19])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCCO)c1
Reactant: COC(=O)[C@@H](N)CC(C)C
Product: COC(=O)C(CC(C)C)NC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cccc(OC)c2)c(OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid with L-leucine methyl ester there was obtained methyl 2-[3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoylamino]-4-methyl-pentanoate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[S:24][C:25]([CH2:33][CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12].CO.C1COCC1.[Li+].[OH-]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[S:24][C:25]([CH2:33][CH2:34][CH2:35][O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylate in 1:1 MeOH and THF (2 mL) was added LiOH (5 mg, 0.21 mmol) dissolved in water (2 mL). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To this crude material was added water and MeOH and allowed to sit overnight. The resulting precipitate was filtered and washed with water. To this solid was added water and acetonitrile and lyophilized to give 12 mg of the desired product 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (24). 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.60 (s, 2H), 7.51-7.33 (m, 3H), 7.27 (t, J=8.0, 3H), 7.17 (t, J=7.7, 2H), 6.92 (dd, J=7.5, 14.2, 5H), 4.03 (t, J=6.4, 3H), 3.95 (s, 2H), 3.42 (d, J=7.8, 4H), 2.78 (s, 2H), 2.10 (s, 3H), 1.88 (d, J=9.5, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].[OH2:19]>C(#N)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:14]1[CH2:15][CH2:16][CH:13]([OH:19])[CH2:12]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCN(CC)CC
Reactant: O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(CN2CCC(O)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25 mL round bottom was charged with 1-(bromomethyl)-3-nitrobenzene (542 mg, 2.509 mmol) pyrrolidin-3-ol (0.813 mL, 10.04 mmol), and triethylamine (1.399 mL, 10.04 mmol) in acetonitrile (5 mL). The resulting solution was stirred overnight at ambient temperature then poured into water (150 mL) and extracted with CH2Cl2 (4×30 mL). The extracts were washed with sat. NaHCO3 solution, H2O and brine. The organic layer was then dried (Na2SO4) and concentrated in vacuo, yielding the title compound. MS (ESI(+)) m/e 222.9 (M+H)+.