Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate(200 mg, 0.7 mmol) and 1-(3,5-dimethylphenyl)piperazine(154 mg 0.7 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(106 mg) was added thereto. The mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>O1CCCC1>[C:33]([N:8]([CH2:7][C:6]1[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccccc1CNc1ccccc1Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1OC(C)C)c1ccccc1Oc1ccccc1

Procedure:
In 30 ml of tetrahydrofuran were dissolved 2.65 g of N-(2-isopropoxybenzyl)-2-phenoxyaniline and 1.5 ml of triethylamine, and then 0.8 ml of acetyl chloride was added dropwise to the solution with stirring, followed by stirring for 30 minutes. The reaction mixture was poured to water and extracted with ethyl acetate, and the extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:4) to give 2.92 g of N-acetyl-N-(2-isopropoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: N12CCN(CC1)CC2.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[NH2:21][C@H:22]1[C@@H:34]2[C:35](=[O:38])[O:36][CH2:37][C@H:33]2[C@H:32]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][Si](C(C)(C)C)(C)C)=[C:41]([O:55][CH3:56])[CH:40]=2)[C:31]2[C:23]1=[CH:24][C:25]1[O:29][CH2:28][O:27][C:26]=1[CH:30]=2>ClCCl>[OH:47][C:42]1[C:43]([O:45][CH3:46])=[CH:44][C:39]([C@@H:32]2[C:31]3[C:23](=[CH:24][C:25]4[O:29][CH2:28][O:27][C:26]=4[CH:30]=3)[C@@H:22]([NH:21][C:16](=[O:18])[C:15]3[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=3)[C@@H:34]3[C:35](=[O:38])[O:36][CH2:37][C@@H:33]23)=[CH:40][C:41]=1[O:55][CH3:56]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](NC(=O)c3ccc([N+](=O)[O-])cc3)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
0.4 mmol of 1,4-diazabicyclo[2.2.2]octane and then 0.78 mmol of para-nitrobenzoic acid are added to a solution of 0.6 mmol of the compound obtained in Step 1 in 10 ml of anhydrous dichloromethane. After 7 hours at ambient temperature, the reaction mixture is evaporated and the residue is chromatographed. The isolated product is then dissolved in 50 ml of methanol and Dowex 50X2-200 resin is added. After stirring for 15 hours at ambient temperature, the reaction mixture is filtered and then concentrated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([OH:19])[CH:16]=[CH:15]2)=[C:7]([NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:6]=1)=[O:4].N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([O:19][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:16]=[CH:15]2)=[C:7]([NH:20][CH2:21][CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(2,2-Diphenyl-ethylamino)-9-((1R,4S)-4-hydroxy-cyclopent-2-enyl)-9H-purine-2-carboxylic acid methyl ester (2.80 g, 6.14 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry tetrahydrofuran (30 ml) is added followed by dry pyridine (0.97 g, 12.3 mmol). Ethyl chloroformate (2.66 g, 24.6 mmol) is added slowly and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 ml) and 1M HCl (2×200 ml). The organic layer is washed with water (2×100 ml) and brine (2×100 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, 4% MeOH in dichloromethane). MS (ES+) m/e 528.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:47])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)[C:25]=1[CH2:41][CH2:42][C:43]([O:45]C)=[O:44]>>[C:43]([CH2:42][CH2:41][C:25]1[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:47])=[O:17])([OH:45])=[O:44]
Reactant: COC(=O)CCCCCc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2cccc(CCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-(3-methoxy-3-oxopropyl)-3-[6-[(methylsulfonyl)oxy]hexyl]benzenehexanoic acid methyl ester from the preceding example, followed by saponification, in 16.8% overall yield. The product was a colorless solid, mp 109°-110° C., recrystallized from acetonitrile.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:23][CH2:24][CH2:25][N:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=5)[CH:29]=[CH:28][C:27]4=[O:38])([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:13][CH2:14][C:15]([CH2:23][CH2:24][CH2:25][N:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=5)[CH:29]=[CH:28][C:27]4=[O:38])([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(Cc2ccc3c(c2)OCCO3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(Cc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To 1 mL of an ethanol solution containing 0.10 g of ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 0.15 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 2 hours. Then, more 0.10 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 5 hours. After left to stand at room temperature overnight, the solvent was removed under reduced pressure, water was added, and adjusted to pH 6.7 with 6.0 mol/L hydrochloric acid. The solvent was removed under reduced pressure, and the residue thus obtained was purified by reversed-phase silica gel column chromatography [eluent; acetonitrile:water=3:7] to give 21 mg of 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH:11]=[CH:10][CH:9]=1>C1COCC1.CO.[C].[Pd].[C].[Rh]>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[CH:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH2:11][CH2:10][CH2:9]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3F)C2=N1
Agent: [Pd]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CO
Product: O=S1(=O)CCN2CCCC(c3ccc(-c4ccccc4)cc3F)C2=N1
Temperature: 50 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 9-(3-fluorobiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (200 mg) in THF/methanol (30 mL/30 mL) was added 10% palladium carbon (50 mg). The reaction mixture was stirred under a hydrogen atmosphere at 50° C. for 1 day. 5% Rhodium carbon (100 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by recrystallization (methanol-THF/diisopropyl ether) to give the title compound (154.4 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=O)[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[S:40])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1
Solvent: O
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1

Procedure:
A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 mL), under nitrogen was treated with Lawesson's Reagent (0.202 g, 0.500 mmol), refluxed for 4 h and concentrated in vacuo. The residue was chromatographed on silica gel with mixctures of MeOH—NH4OH—CHCl3 containing 1-10% MeOH and 0.1-0.5% NH4OH and the resulting product was crystallized from MeOH—CHCl3—EtOAc to give 0.0491 g of 3: mip 218.5° C.; HR FAB MS theory for C19H22FN5O4S (M+): 435.1376; found 435.1370. Anal. calcd for C19H22FN5O4S. 0.5 H2O: C, 51.34; H, 5.21; N. 15.76. Found: C, 51.69; H, 5.00; N, 15.25.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].N1C(C)=CC=CC=1C.[H][H]>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: O=Cc1cccc(C2CC=CO2)c1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: OCc1cccc(C2CCCO2)c1
Yield: 70 %

Procedure:
EX-608C) A THF (15 mL) solution of the aldehyde from EX-608B (0.70 g, 4.0 mmol) and 2,6-lutidine (0.46 mL, 4.0 mmol) was stirred in a hydrogen 4.0 mmol) and 2,6-lutidine (0.46 mL, 4.0 mmol) was stirred in a hydrogen temperature. The slurry was filtered through celite, and the solvent was removed. The residue was taken up in ethyl acetate and washed with 1 N HCl and brine. The organic layer was dried (MgSO4) and evaporated to give 0.50 g (70%) of the desired 3-(tetrahydro-2-furanyl)phenylmethanol product as a yellow oil. The formation of the desired product was monitored by the disappearance of the aldehyde (δ˜10) and olefin peaks in the 1H NMR disappearance of the aldehyde (δ˜10) and olefin peaks in the 1H NMR spectrum. 2.8 mmol) and MnO2 (2.10 g, 24.3 mmol) in dichloromethane (15 mL) was refluxed for 3 h. The slurry was filtered through celite, and the filtrate was evaporated to a yellow oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave 0.19 g (45%) of the desired aldehyde product as a pale yellow oil. GCMS: m/z=177 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)([CH3:26])[CH:22]([CH3:35])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([CH3:26])([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]3[N:34]=[N:7][NH:6][C:5]=3[Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:28]=2)[CH:22]([CH3:35])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(C)c1cccc(C#N)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1(C)c1cccc(-c2nn[nH]c2[Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 9.86 mL, 19.7 mmol) in tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added n-butyllithium (2.5 M in hexane, 7.9 mL, 19.7 mmol) dropwise. After 30 min, a solution of 1-benzyl-4-(3-cyanophenyl)-3,4-dimethylpiperidine (Preparation 3, 5.0 g, 16.4 mmol) in tetrahydrofuran (40 mL) was added such that the internal temperature remained at 0° C. After stirring overnight, the reaction was quenched with saturated aqueous sodium hydrogencarbonate (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale brown foam (6.53 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:35])[CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH:48]=[CH:47][N:46]=[C:45]([C:49](O)=[O:50])[C:44]2=[O:52])=[CH:39][CH:38]=1>>[F:35][C:4]1[CH:3]=[C:2]([NH:1][C:49]([C:45]2[C:44](=[O:52])[N:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[CH:48]=[CH:47][N:46]=2)=[O:50])[CH:34]=[CH:33][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:8]=12
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Yield: 53 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to the procedure of Example 101, Step B. The crude was rinsed with Et2O to afford 8.8 mg (53%) of the desired product. LRMS (ESI pos) m/e 573.0 (M+1). 1H NMR (400 MHz, CD3OD/CDCl3) δ 8.14 (d, 1H), 8.05 (dd, 1H), 7.86 (m, 2H), 7.57 (m, 2H), 7.51 (d, 1H), 7.34 (m, 3H), 6.12 (d, 1H), 3.71 (m, 1H), 2.92 (m, 2H), 2.35 (s, 3H), 2.29 (m, 2H), 2.22 (m, 2H), 1.65 (m, 2H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −112.1, −129.4.
Reaction SMILES: [CH:1]([OH:3])=O.CC(OC(C)=O)=O.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][CH:1]=[O:3])[CH:16]=[CH:17][CH:18]=1
Reactant: O=CO
Reactant: Nc1cccc(Br)c1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=CNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
A solution of formic acid (24.3 g, 98%, 528 mmol) in Ac2O (43.94 g, 430 mmol) was heated to 55° C. for 2 hours, cooled to room temperature. The mixture was diluted with toluene (25 mL) followed by the addition of of 3-bromoaniline (28 g, 163 mmol) in toluene (40 mL). The solution was stirred cold for 30 minutes after which the solvents were removed under vacuo and the residue crystallized from hexane to give N-(3-bromophenyl)formamide (32.79 g). The material was added in portions to 1M. BH3 in THF (450 mL) at 0° C., heated to refluxing for 3 hours and cooled to ambient temperature. The solvents were removed under reduced pressure, the residue was treated with aqueous hydrochloric acid (1M, 200 mL) for for ½ hour, the pH was adjusted to 12 with the addition of sodium hydroxide (1M). The solution was extracted with diethyl ether (3×75 mL), the combined ether layers dried (MgSO4, filtered and concentrated under reduced pressure to give the titled compound (29.48).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:18])[NH:6][C:7](=[O:17])[N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)(=[O:3])[CH3:2].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:6]2[C:5](=[O:18])[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][N:8]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]2=[O:17])=[CH:22][CH:21]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(=O)c1cn(Cc2ccccc2)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccc(F)cc2)c1=O
Yield: 93.7 %

Procedure:
The title compound was synthesized in 93.7% yield by benzylation of 5-acetyl-1-benzyluracil (2e) with 2 equiv of 4-fluorobenzyl bromide and 2 equiv of potassium carbonate in DMF. Mp. 106-108° C. 1HNMR (CDCl3): 8.23 (s, 1H), 7.30-7.50 (m, 7H), 7.00 (m, 2H), 5.12 (s, 2H), 5.01 (s, 2H), 2.61 (s, 3H). 13CNMR (CDCl3): 194.3, 162.4 (d, J=246.4 Hz), 160.7, 151.0, 148.4, 134.4, 132.1 (d, J=3.4 Hz), 131.1 (d, J=8.2 Hz), 129.2, 128.9, 128.2, 115.3 (d, J=21.6 Hz), 112.3, 53.4, 44.2, 30.6. FAB-HRMS: [M+H]+ calcd. for C20H18FN2O3 353.1301, found 353.1310.
Reaction SMILES: [CH3:1][C:2]([N+:17]([O-:19])=[O:18])([CH2:15][CH3:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.[H-].[Na+].[CH3:22]I>CN(C)P(=O)(N(C)C)N(C)C>[CH3:22][N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:4]([CH2:3][C:2]([CH3:1])([N+:17]([O-:19])=[O:18])[CH2:15][CH3:16])=[CH:5]1
Reactant: CCC(C)(Cc1c[nH]c2ccc(OC)cc12)[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C)(Cc1cn(C)c2ccc(OC)cc12)[N+](=O)[O-]

Procedure:
If the 3-(2'-methyl-2'-nitrobutyl)-5-methoxy-indole obtained as intermediate product in Example 2 is methylated by the procedure described in Example 4 (or by means of sodium hydride and methyl iodide in hexamethyl phosphoric acid triamide), 1-methyl-3-(2'-methyl-2'-nitrobutyl)-5-methoxy-indole is obtained and melts at 95°-96°C. after crystallisation from acetone/water and distillation. Catalytic reduction thereof yields 1-methyl-3-(2'-methyl-2'-aminobutyl)-5-methoxy-indole. Melting point of the benzoic acid salt 179.5°-184°C. (insoluble in ether).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]([C:18](Cl)=[O:19])[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]([C:18]([NH:29][C:28]([NH2:30])=[NH:27])=[O:19])[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(N)N
Reactant: O=C(Cl)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: O=C(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N=C(N)NC(=O)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 20.3 %

Procedure:
To a suspension of 7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl chloride (0.360 g., 1 mmol) in 20 mL acetonitrile, was added guanidine carbonate (0.180 g., 1 mmol), followed by the dropwise addition of N,N-diisopropyl ethylamine (0.523 mL, 3 mmol.) The reaction mixture was partitioned between 50 mL each of water and ethyl acetate. The organic fraction was washed with dilute aqueous hydrogen chloride followed by 50 mL water. The organic fraction was dried over sodium sulfate and concentrated in vacuo. The resulting white solid was dissolved in 20 mL refluxing dichloromethane. On cooling, white crystals formed, which were filtered and dried under vacuum to give 73 mg (21 %) of N-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-guanidine free base, which recrystallized from EtOH/HCl/Et2O to provide the hydrochloride salt. MS: 361 (M+H)+, mp (as hydrochloride): 148.5-151.6° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[C:32]1([CH2:38][CH2:39][CH2:40][N:41]=[C:42]=[S:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:42]([NH:41][CH2:40][CH2:39][CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[S:43])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: S=C=NCCCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(NC(=S)NCCCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
An equimolar solution of N-(toluene-4-sulfonyl)-L-prolyl-4-amino-L-phenylalanine methyl ester and 3-phenylpropyl isothiocyanate in toluene was stirred at room temperature for 16 hr. The solvent was stripped off giving an amber oil which was submitted to preparatory HPLC (Waters silica cartridge; 85/15 CH2Cl2/EtOAc) for purification. The fractions were collected and the solvent removed yielding the title compound as a white solid, mp=74-80° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([F:26])=[C:20]([CH:23]=[CH:24][CH:25]=4)[CH:21]=[O:22])=[CH:14][N:13]3[CH:27]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([F:26])=[C:20]([CH2:21][OH:22])[CH:23]=[CH:24][CH:25]=4)=[CH:14][N:13]3[CH:27]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
162 mg of sodium borohydride are added portionwise to 150 mg of 3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-2-fluorobenzaldehyde dissolved in 20 ml of methanol. The mixture is subsequently stirred at ambient temperature for 2 hours and then the solvent is evaporated under reduced pressure. The residue is taken up between water and dichloromethane and the organic phase is separated, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol 98/02 mixture. 87 mg of compound are obtained.