Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(NC(=O)C2C=CC=NC=2NC2CC(C)(C)NC(C)(C)C2)C=CC=1.[CH2:51](Cl)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.BrCCO>>[CH2:51]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:23])[CH2:18]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCNC1
Reactant: ClCc1ccccc1
Agent: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Agent: OCCBr
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCN(Cc2ccccc2)C1
Yield: 68.2 %

Procedure:
The title compound was prepared in the same manner as in Example 21, with the exception that (S)—N-(3-chlorophenyl)-2-(3-piperidylamino)nicotinamide of Example 20-B, instead of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide, and benzylchloride, instead of 2-bromoethanol, were used in the same molar amounts (Yield: 68.2%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7]C)=[O:6].[CH:14](O)=O>>[CH3:13][C:3]1[C:2]2[NH:1][CH:14]=[N:12][C:11]=2[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=CO
Reactant: COC(=O)c1ccc(N)c(N)c1C
Product: Cc1c(C(=O)O)ccc2nc[nH]c12
Temperature: 70 °C

Procedure:
Methyl 3,4-diamino-2-methylbenzoate (synthesized in reagent preparation 22) (0.18 g, 1.0 mmol) was taken up in formic acid (8.0 mL) and refluxed for 4 hours. The solution was then concentrated in vacuo. The material was taken up in methanol (2.5 mL) and tetrahydrofuran (5.0 mL) and treated with 2M aqueous lithium hydroxide (2.5 mL) and heated to 70° C. for 12 hours. This solution was made acidic using concentrated aqueous hydrochloric acid, then extracted with 10% methanol in ethyl acetate (2×50 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to give 0.055 g of 7-methyl-1H-benzimidazole-6-carboxylic acid. 1H NMR (400 MHz, d6-DMSO): 9.34 (s, 1H), 7.94 (d, 1H), 7.64 (d, 1H), 2.85 (s, 3H). MS (EI) for C9H8N2O2: 177 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]([C:21]([F:24])([F:23])[F:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:30][O+](C)C>>[CH3:30][O:20][C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([C:21]([F:22])([F:23])[F:24])[N:10]=2)[N:19]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(Cc2nc(C(F)(F)F)nn2-c2ccccc2)N1
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2nc(C(F)(F)F)nn2-c2ccccc2)CCCC1

Procedure:
The product of Example 152 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]1([O:13][C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[C:20]3[CH2:27][C:28]2[CH:51]=[CH:50][C:31]([C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]#[C:45][C:46]([OH:49])([CH3:48])[CH3:47])(=[O:37])=[O:36])=[O:33])=[CH:30][C:29]=2[O:52][CH3:53])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[CH:8]1([O:13][C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[C:20]3[CH2:27][C:28]2[CH:51]=[CH:50][C:31]([C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]#[C:45][C:46]([O:49][C:1](=[O:3])[CH3:2])([CH3:48])[CH3:47])(=[O:36])=[O:37])=[O:33])=[CH:30][C:29]=2[O:52][CH3:53])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CC(C)(C)O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CC(C)(C)OC(C)=O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.44 g of acetic anhydride and 0.1 g of 4-dimethylaminopyridine are added to a solution of 1.0 g of N-[4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-yl-methyl]-3-methoxybenzoyl]-2-(3-hydroxy-3-methyl-but-1-yn-1-yl)-benzenesulfonamide in 6 ml of pyridine. The reaction solution is stirred for 20 hours at room temperature under argon. The reaction mixture is subsequently diluted with 100 ml of ethyl acetate. The ethyl acetate phase is washed twice with 80 ml of 1N hydrochloric acid each time, with 50 ml of water and with 50 ml of saturated sodium chloride solution. The ethyl acetate phase is dried over magnesium sulfate and concentrated by evaporation at 20 torr and 40°. The residue is chromatographed on 50 g of silica gel (Merck, ST 60, 40-63 μm) with hexane/ethyl acetate=1/1 to yield the title compound in the form of a white amorphous solid. 1H-NMR (400 MHz, DMSO-d6): 8.87 (b, 1H); 8.06 (d, d, 1H); 7.61 (m, 3H); 7.55 (d, 1H); 7.50 (d, 1H); 7.41 (d, d, 1H); 7.22 (d, 1H); 7.14 (d, d, 1H); 7.13 (d, 1H); 6.94 (s, 1H); 5.06 (m, 1H); 3.95 (s, 2H); 3.90 (s, 3H); 3.66 (s, 3H); 1.91 (s, 3H); 1.89-1.52 (m, 8H); 1.61 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][N:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[C:22]2[CH:34]=[CH:35][N:36]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:21]=2[C:20]1=[O:47]>>[CH3:18][N:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][CH:8]=[N:7][C:6]=3[C:10]=2[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:22]2[CH:34]=[CH:35][N:36]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:21]=2[C:20]1=[O:47]
Reactant: Brc1ccc2ocnc2c1Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5ocnc5c4Oc4ccccc4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-4-phenoxy-1,3-benzoxazole and 6-methyl-1[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C28H22N3O5S (M+H)+: m/z=512.1. found: 512.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: OCC1CCN(c2ncc(F)cn2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC1CCN(c2ncc(F)cn2)CC1

Procedure:
1-(5-Fluoro-2-pyrimidinyl)-4-piperidinecarbaldehyde (0.96 g, 60%) was prepared as a white solid from [1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]methanol (prepared as in Example 152, Step 1, 1.62 g, 7.67 mmol) and PCC (pyridinium chlorochromate, 2.53 g, 11.50 mmol) in CH2Cl2 (36 mL) in a manner similar to Example 146, Step 1. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 20% EtOAc/hexanes to give 1-(5-fluoro-2-pyrimidinyl)-4-piperidinecarbaldehyde as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.68 (s, 1H), 8.20 (s, 2H), 4.55-4.45 (m, 2H), 3.25-3.10 (m, 2H), 2.60-2.45 (m, 1H), 2.05-1.90 (m, 2H), 1.70-1.55 (m, 2H); LRMS (ESI), m/z 210 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>[Pd].C1COCC1.CO>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(-c2ccc(OC)c(O)c2)n1

Procedure:
In a mixed solvent of THF-methanol, methyl 6-(3-benzyloxy-4-methoxyphenyl)pyridine-2-carboxylate was stirred in the presence of palladium/carbon under a hydrogen atmosphere to obtain methyl 6-(3-hydroxy-4-methoxyphenyl)pyridine-2-carboxylate. The obtained compound is reacted with cyclopropylmethyl bromide and potassium carbonate in DMF under heating to obtain methyl 6-(3-cyclopropylmethoxy-4-methoxyphenyl) pyridine-2-carboxylate, which was further reacted in a mixed solvent of THF-methanol under heating with adding a 1M aqueous sodium hydroxide solution to obtain an objective compound.
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]([CH:11]1[CH2:15][S:14](=[O:17])(=[O:16])[CH2:13][N:12]1C(OC(C)(C)C)=O)(=[O:10])[NH2:9]>ClCCl>[ClH:1].[O:16]=[S:14]1(=[O:17])[CH2:15][CH:11]([C:8]([NH2:9])=[O:10])[NH:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CS(=O)(=O)CC1C(N)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)C1CS(=O)(=O)CN1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
An ice cold 4 M solution of HCl in dioxane (4.73 mL, 18.9 mmol) was added to a solution of tert-butyl 4-carbamoyl-1,1-dioxo-1,3-thiazolidine-3-carboxylate (Example 127 c, 500 mg, 1.89 mmol) in dichloromethane (10.2 mL). The mixture was stirred for 4 d at ambient temperature. Removal of the solvent in vacuo yielded the title compound (388 mg, quant.) as white solid which was used in the next step without further purification, MS (ESI) m/e=198.99 [M−H−].
Reaction SMILES: [NH2:1][NH2:2].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.O>CO>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]([NH:1][NH2:2])=[O:4])=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)Cc1ccc(O)cc1
Temperature: 52.5 °C
Reaction time: 1 h

Procedure:
Neat anhydrous hydrazine 21.0 g (654 mmol) was added to a solution of p-hydroxyphenylacetic acid methyl ester 27.18 g (163.5 mmol) in MeOH (100 mL) and the mixture was heated to 50-55° C. and stirred at this temperature for 90 min (water bath). Cooled, stirred for extra 1 hour, the precipitate collected by filtration, compressed on the frit, washed with MeOH (3×10 mL) and dried on high vacuum. A second fraction was obtained by cooling the supernatants to −15° C. overnight and filtering the formed precipitate.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[N:33]([CH3:34])[C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:34][N:33]1[C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[N:30]=[C:29]1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cn1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (460 mg), 2-chloromethyl-1-methyl-1H-benzimidazole (250 mg), potassium carbonate (360 mg) and N,N-dimethylformamide (15 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (550 mg, yield: 85%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][C:15]([NH:18]C(=O)OCC1C=CC=CC=1)([CH3:17])[CH3:16])(=[O:12])=[O:11]>CO.[Pd]>[NH2:18][C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][S:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])(=[O:12])=[O:11]
Reactant: CC(C)(CCS(=O)(=O)CCOCCOCCO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CCOCCOCCO
Reaction time: 1 h

Procedure:
To a solution of benzyl 4-(2-(2-(2-hydroxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (223 mg, 0.534 mmol) in methanol (5 ml) was added palladium on carbon (10%, 35 mg). The suspension was put under a N2 atmosphere and H2 (1.3 atmospheres) introduced. The suspension was stirred for 1 hour, filtered (0.45 um, PTFE), and concentrated in vacuo. The residue was used without any further purification. LRMS (ESI/APCI) m/z 284 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH3:12])=[C:7]([NH2:13])[N:6]=1)=[O:4].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:13][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[N:9][C:8]=1[O:11][CH3:12])(=[O:24])=[O:23]
Reactant: COC(=O)c1cnc(OC)c(N)n1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: COC(=O)c1cnc(OC)c(NS(=O)(=O)c2cccc(Cl)c2Cl)n1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 6-amino-5-methoxypyrazine-2-carboxylic acid methyl ester (Example 201b) (0.3 g) and 2,3-dichlorobenzenesulphonyl chloride (0.4 g). Yield 0.15 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][C@@H:21]([CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][C:24](O)=[O:25])[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1[CH:33]=[CH:34][C:35]2N(O)N=[N:38][C:36]=2C=1.C(N)CCC.C(Cl)CCl>CN(C)C=O.C(Cl)Cl>[CH2:36]([NH:38][C:24](/[CH:23]=[CH:22]/[C@H:21]([CH:27]([CH3:28])[CH3:29])[CH2:20][C@@H:11]1[O:10][C:9]([CH3:31])([CH3:30])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:12]1[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:25])[CH2:35][CH2:34][CH3:33]
Reactant: On1nnc2ccccc21
Reactant: CC(C)[C@@H](C=CC(=O)O)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCCCN
Product: CCCCNC(=O)/C=C/[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
A mixture of 0.55 g (1.26 mmol) of (S)-5-[(4S,5S)-3-(t-butoxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-oxazolidinyl]-4-isopropyl-2-pentenoic acid, 0.22 g (1.6 mmol) of HOBT, 0.14 ml (1.4 mmol) of butylamine and 8 ml of methylene chloride is cooled to 0° and treated dropwise with a solution of 0.29 g (1.5 mmol) of EDC in 2 ml of dimethylformamide. Thereafter, the reaction mixture is stirred at 0° for 1 hour and subsequently at room temperature for 16 hours and then poured into ice-water and extracted with methylene chloride. The methylene chloride extracts are dried over potassium carbonate and evaporated under reduced pressure. Chromatography of the residue obtained on 10 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 0.53 g of t-butyl (4S,5S)-5-[(S,E)-4-(butylcarbamoyl)-2-isopropyl-3-butenyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a pale yellow oil which is used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][CH2:7]2)[CH3:2].OO.S(=O)(=O)(O)[OH:15]>C(O)=O>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:15])[CH2:7]2)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCc1cccc2c1C=CC2
Agent: OO
Solvent: O=CO
Product: CCc1cccc2c1CC(=O)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59 %

Procedure:
33.9 g (235 mmol) of 4-ethylindene (a2) were slowly added dropwise to a mixture of 141 ml of formic acid (98-100% strength) and 33 ml (340 mmol) of H2O2 (35% strength), while cooling with ice (highly exothermic reaction). The mixture was then stirred at room temperature for a further 2.5 hours. The yellow-orange suspension formed was freed from excess formic acid under a water pump vacuum. 900 ml of 2N sulfuric acid were added to the yellow oil which remained. A total of 3 l of water were distilled over, while topping up with water, the product separating out in the receiver as a yellowish oil. The distillate was neutralized with saturated sodium carbonate solution and extracted with ether. The ether phase was dried over sodium sulfate and evaporated. 22.4 g (59%) of the compound a3 were obtained as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([F:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)O1>>[F:14][C:9]1[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]([C:27]2[CH:41]=[CH:40][C:30]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:29][CH:28]=2)=[C:11]([O:12][CH3:13])[CH:10]=1
Reactant: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 44 %

Procedure:
Following General Procedure B, 9-bromo-6-fluoro-8-methoxythieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.50 mmol) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (200 mg, 0.60 mmol) to afford the desired product (100 mg, 48%) as a brown solid: ESI MS m/z 455 [C24H23FN2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].C[O:13]CCOCCO.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:13])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCOCCO
Reactant: O=Cc1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c(O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 2-chloro-4,5-difluoro-benzaldehyde (110, 0.40 g, 2.30 mmol, prepared as described in Example 37) in N,N-dimethylformamide (10.0 mL) were added 2-(2-methoxyethoxy)-ethanol, (0.327 g, 2.72 mmol) and cesium carbonate (0.886 g, 2.72 mmol). The reaction was stirred at 90° C. overnight. The reaction was poured into water, acidified to pH around 5, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (111, 0.24 g, 61.0%). MS (ESI) [M+H+]+=173.1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)CCCN1CCN(C(=O)CCNC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCN1CCN(C(=O)CCN)CC1
Yield: 42.3 %

Procedure:
To methyl 4-{4-[N-(tert-butoxycarbonyl)-beta-alanyl]piperazin-1-yl}-butanoate (290 mg, 0.8 mmoles) in 2 mL dichloromethane was added 2 mL trifluoroacetic acid. After 1 hour the solvents were evaporated. The residue was dissolved in 10% DMF/DCM and MP-carbonate (0.8 g) was added. After 16 h the solution was filtered and evaporated to afford methyl 4-(4-beta-alanylpiperazin-1-yl)butanoate (87 mg, 41%) as an oil. MS (ESI+) for m/z 272 (M+H)+.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+]>CO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][CH:16]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCN1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of tert-butyl 3-(3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidin-1-yl)propanoate (65 mg, 0.148 mmol) in methanol (2 mL) was added sodium hydroxide (6M, 0.3 mL, 1.800 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 28 mg of product (HCl salt) as off-white solid. MS: (M+H)+=289.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.43 (q, 1H), 1.58-1.74 (m, 1H), 2.01 (s, 1H), 2.38 (br. s., 1H), 2.62 (m, 1H), 2.87-3.13 (m, 4H) 3.25-3.68 (m, 8H), 7.18-7.44 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][S:3]1.Cl.[NH2:15][OH:16].N1C=CC=CC=1>C(O)C>[CH3:1][C:2]1([CH3:13])[C:11](=[N:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][S:3]1
Reactant: NO
Reactant: CC1(C)SCc2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC1(C)SCc2ccccc2C1=NO
Yield: 55.7 %

Procedure:
A mixture of 10.0 g of 3,3-dimethylisothiochroman-4-one, 8.0 g of hydroxylamine hydrochloride, 18 ml of pyridine and 60 ml of ethanol is heated at reflux for 60 hours. The cooled reaction mixture is concentrated by evaporation, then toluene is added and the mixture is again concentrated by evaporation. The residue is boiled up in dichloromethane, cooled and filtered. The filtrate is concentrated by evaporation and the residue is chromatographed with silica gel (eluant: ethyl acetate/hexane 1:12). Concentration of the eluate by evaporation yields 6.0 g of 3,3-dimethylisothiochroman-4-oneoxime in the form of yellow crystals having a melting point of 83°-84° C.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C)C=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[N:43]1([CH2:42][CH2:41][NH:40][C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NCCN1CCCC1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (250 mg, 1.63 mmol) in dimethylformamide (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (376 mg, 1.2 equiv.), 1-hydroxybenzotriazole (265 mg, 1.2 equiv.), triethylamine (0.45 mL, 2 equiv.) and 1-(2-aminoethyl)pyrrolidine (0.23 mL. 1.1 equiv.). After stirring at room temperature overnight, the reaction was diluted with saturated sodium bicarbonate and brine (with extra salt) and extracted with 10% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 130 mg of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide.