Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.O.Cl.[CH2:14](OCC)C>>[CH3:14][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: CC1Cc2ccccc2C1=O
Reactant: CCOCC
Agent: Cl
Solvent: O
Product: CC1=Cc2ccccc2C1C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 15.02 g (103 mmoles) of (+/-)-2-methyl-1-indanone in 200 mL of anhydrous diethyl ether at -78° C. under an argon atmosphere was injected 50 mL of a 3.0 M methylMgl solution in ether (150 mmoles MeMgl). The reaction was allowed to slowly warm to room temperature over three hours and then it was heated at 35° C. for 1 hour. The reaction was poured into 1L of water, and concentrated HCl was slowly added until a pH of 1 was achieved. The mixture was transferred to a separatory funnel and shaken vigorously. The layers were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with water (1×500 mL), with aqueous NaHCO3 (1×500 mL), and with saturated aqueous NaCl (1×500 mL). The organic layer was dried over anhydrous MgSO4 and filtered. GC showed that some alcohol was still present so the mixture was stirred with approximately 100 ml of 10 weight percent aqueous HCl for 1 hour. The mixture was transferred to a separatory funnel, and the layers were separated. The organic phase was washed with water (1×200 mL), with aqueous NaHCO3 (1×300 mL), and with saturated aqueous NaCl (1×250 mL). Drying over MgSO4 followed by filtration and solvent removal yielded 14.7 g (99 percent) of 1,2-Dimethylindene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH3:18].O.O.Cl[Sn]Cl.CCO>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOc1ccc(N)cc1-c1c(Br)cnn1C

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenylamine was prepared in a similar manner as described in Example 1.1 using 4-bromo-5-(2-ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole, SnCl2.2H2O in EtOH [0.225 g, 0.76 mmol, 81% for three steps from 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol]. LCMS m/z (%)=296 (M+H79Br, 100), 298 (M+H81Br, 98). 1H NMR (400 MHz, CDCl3) δ: 7.52 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.77 (dd, J=2.2, 8.5 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 3.82-4.00 (m, 2H), 3.73 (s, 3H), 3.24-3.58 (broad s, 2H), 1.24 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[N:18]1([CH2:24][CH2:25][C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[C:28]([C:35](Cl)=[O:36])[N:27]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:35]([C:28]2[N:27]=[C:26]([CH2:25][CH2:24][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=23)=[O:36])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To a solution of 4-chlorobenzylamine (0.080 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (85 mg, 47%). 1H NMR (DMSO-d6) δ 8.52 (1H), 8.35 (1H), 8.05 (1H), 7.35 (4H), 7.08 (1H), 6.85 (1H), 4.45 (2H), 3.58 (4H), 3.20 (2H), 2.78 (2H), 2.45 (4H); m/z (M+H)=399.16.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]2[N:7]([CH3:12])[C:6]3[CH2:13][CH:14]4[NH:18][CH:17]([C:5]=3[C:4]=2[C:3]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]4.[C:26]1([S:32](C2C=CC=CC=2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([C:2]2[CH:10]=[C:9]([Cl:11])[C:8]3[N:7]([CH3:12])[C:6]4[CH2:13][CH:14]5[NH:18][CH:17]([C:5]=4[C:4]=3[C:3]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]5)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)cc(Cl)c31)C1CCC(C2)N1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)cc(Cl)c31)C1CCC(C2)N1
Yield: 63 %

Procedure:
The product of step E was converted to the phenylsulfone derivative following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 75:25 hexanes/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-4-chloro-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (165 mg, 63%) as an off-white solid: 1H NMR (CDCl3, 300 MHz): δ 8.02-8.07 (m, 1H), 7.91-7.97 (m, 2H), 7.42-7.62 (m, 4H), 5.10-5.32 (m, 1H), 4.55-4.80 (m, 1H), 3.94 (s, 3H), 3.15-3.48 (m, 1H), 2.47 (d, J=16.2 Hz, 1H), 2.10-2.40 (m, 2H), 1.85-1.96 (m, 1H), 1.52-1.65 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:33][C:17]3=[N:18][CH:19]=[C:20](Br)[C:21]([NH:22][C:23]4[CH:31]=[CH:30][C:26]5[N:27]=[CH:28][S:29][C:25]=5[CH:24]=4)=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:35](#[N:37])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:33][C:17]3=[N:18][CH:19]=[C:20]([C:35]#[N:37])[C:21]([NH:22][C:23]4[CH:31]=[CH:30][C:26]5[N:27]=[CH:28][S:29][C:25]=5[CH:24]=4)=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)c(Br)cnc3[nH]2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)c(C#N)cnc3[nH]2)CC1

Procedure:
To a mixture of 4-[4-(benzothiazol-6-ylamino)-5-bromo-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (20 mg, 0.038 mmol), DPPF (10.1 mg, 0.018 mmol), water (0.04 mL) and zinc cyanide (8.9 mg, 0.075 mmol) in acetonitrile-(4 mL) was added Pd2 dba3 (7.0 mg, 0.007 mmol) and the mixture was heated to reflux under N2 overnight. The reaction mixture was evaporated, and the crude product was purified by preparative TLC using 7% methanol in DCM as eluent to afford the title compound as light gray solid. 1H NMR (400 MHz, CDCl3): δ=8.98 (s, 1H), 8.22 (s, 1H), 8.10 (d, J=8.6 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.36 (dd, J=8.6, 2.1 Hz, 1H), 6.95 (s, 1H), 5.93 (bs, 1H), 5.36 (s, 1H), 3.99-4.02 (m, 2H), 3.44 (t, J=5.7 Hz, 2H), 3.42 (d, J=4.9 Hz, 2H), 2.07-2.12 (m, 2H), 1.39 (s, 9H); MS (ES+): m/z 472.96 (100) [MH+]; HPLC: tR=3.25 min (ZQ2000, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[CH:12]([OH:17])[CH2:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.S(=O)(=O)=O.N1C=CC=CC=1.CS(C)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[C:12](=[O:17])[CH2:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CC3CC(O)C2C3)cc1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CC2CC1N(c1ccc([N+](=O)[O-])cc1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a round bottom flask was added 2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-ol (150 mg, 0.640 mmol), Et3N (0.446 mL, 3.20 mmol) and CH2Cl2 (3 mL). The reaction was cooled to 0° C. Pyridine sulfur trioxide (510 mg, 3.20 mmol) and DMSO (0.909 mL, 12.81 mmol) were mixed in a vial until the solution turned clear and then this clear solution was added to the reaction mixture at 0° C. The reaction was slowly warmed to rt and stirred at rt for 2 hrs. The reaction was diluted with CH2Cl2 (25 ml). The organic solution was washed with water (2×20 ml) and saturated aqueous NaCl (20 ml). The organic layer was dried with MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-one, (80 mg, 0.344 mmol, 54% yield) as a yellow solid. Anal. Calcd. for C12H12N2O3 m/z 232.2, found: 233.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: COC(=O)c1ccc2c(ccn2Cc2ccc([N+](=O)[O-])cc2)c1

Procedure:
1-(4-Nitro-benzyl)-1H-indole-5-carboxylic acid methyl ester was prepared from 1H-indole-5-carboxylic acid methyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow poder: 1H NMR (DMSO-d6) δ 3.84 (s, 3H), 5.67 (s, 2H), 6.71 (dd, J=3.2, 0.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.67 (d, J=0.8 Hz, 1H), 7.73 (dd, J=8.8, 1.7 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H), 8.29 (d, J=1.0 Hz, 1H); MS (ESI) m/z 311 (MH+), 309 ([M−H]−); HRMS calcd for C17H15N2O4: 311.1030; found (ESI+): 311.1021.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.O>C1(C)C=CC=CC=1>[CH3:5][C:4]1[CH2:11][C:1]2[C:6]([CH:3]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:5]1[C:6]2[C:1](=[CH:11][CH:2]=[CH:1][CH:6]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=Cc2cccc(-c3cccc4ccccc34)c2C1
Yield: 4030.6 %

Procedure:
The crude product was taken up in 200 cm3 of toluene, 0.5 g of p-toluene sulfonic acid was added, the reaction mixture was refluxed for 2 hours on a water separator and washed 3 times with 50 cm3 of saturated aqueous NaHCO, solution, and the solvent was removed in vacuo. Filtration through 200 g of silica gel (hexane/methylene chloride) gave 10 g (86%) of 22 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][CH2:29][CH2:28][C:27]1=[O:37]>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([N:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:26][C:27](=[O:37])[CH2:28][CH2:29]1)=[O:8]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=C1CCNc2ccccc2N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(=O)Nc3ccccc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid (800 mg) and catalytic amount of N,N-dimethylformamide in dichloromethane (8 ml) was added oxalyl chloride (0.7 ml) at 0° C. and the solution was stirred at ambient temperature for 30 minutes followed by the removal of solvents to give a crude acid chloride. To a solution of 1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (658 mg) and triethylamine (821 mg) in dichloromethane (4 ml) was added a solution of the above acid chloride in dichloromethane (4 ml) at ambient temperature and the mixture was stirred at ambient temperature for 1 hour. The resultant mixture was filtered and the solid was washed with water and diethyl ether to give 5-(3-methoxy-4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.29 g) as a colorless prisms.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]1[O:23][C@H:22]1[CH2:24][OH:25].C(N(CC)CC)C>C(Cl)Cl>[C:2]1([C:1]([O:25][CH2:24][C@H:22]2[O:23][CH2:21]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 130.9 %

Procedure:
A solution of trityl chloride (48.25 g, 173 mmol) in anhydrous CH2Cl2 (150 mL) was added to a stirred solution of (S)-(−)-glycidol (12.21 g, 164 mmol) and triethylamine (34.5 mL, 247 mmol) in anhydrous CH2Cl2 (250 mL) at −20° C. under a N2 atmosphere. After 2 h, CH2Cl2 was removed under vacuum. The mixture was taken up in EtOAc (500 mL) before it was washed with H2O (2×200 mL). The organic layer was dried, filtered and concentrated to give the crude title compound (67.9 g) contaminated with trityl alcohol, which can be removed by chromatography.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=O)[CH3:2].[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14]=[C:15]=[S:16])[CH2:8][CH2:7]1>C(O)C>[CH3:2][C:1]1[N:14]([CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][O:6][CH2:11][CH2:10]2)[C:15]([SH:16])=[N:5][N:4]=1
Reactant: S=C=NCCN1CCOCC1
Reactant: CC(=O)NN
Solvent: CCO
Product: Cc1nnc(S)n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.2 %

Procedure:
The title compound was prepared by a modification of a procedure reported for related compounds: Henichart, J. P.; Bernier, J. L. Synthesis 1980, 4, 311. Acetic hydrazide (3.7 g, 50 mmol) in ethanol (50 mL) was placed in a 200 mL 3-necked round bottomed flask outfitted with a magnetic stir bar and a reflux condenser. 2-morpholinoethyl isothiocyanate (8.61 g, 500 mmol) in ethanol (50 mL) was added to the pot. The mixture was refluxed, under N2, for 6 h. The reaction was cooled to room temperature and the solvent removed on the rotovap. The resulting resin was dissolved in minimal ethanol and ether. A white solid precipitated out, was filtered and washed with cold ether. The filtrate, containing uncyclized intermediate, was concentrated and dissolved in xylenes. The mixture was refluxed under N2 for 8 h, then allowed to sit at room temperature, under N2. for 48 h. A white solid formed, was filtered and washed with cold ether. The first and second batches of white solid were combined to yield 7.33 g (64%) of the desired product. 1H NMR (DMSO-d6): d 2.33 (s, 3H) 2.41 (m, 4H) 2.55 (m, 2H) 3.52 (m, 4H) 3.99 (t, 2H, J=6) 13.41 (s, 1H). MS (APCI) calcd for C9H16N4OS: 228.32; found (M+H+) 229.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:16]1([S:22][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Reactant: Sc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Sc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (1.0 g, 0.005 mol) in dry toluene (5 ml) was treated with thiophenol (0.55 g, 0.005 mol) and a catalytic amount of p-toluenesulfonic acid monohydrate (25 mg). The mixture was heated at 60° C. for 2 h and then at 80° C. for a further 5 h. The reaction was diluted with diethyl ether and washed with 5% NaOH (3×10 ml) followed by water (10 ml) and brine (10 ml). The organic phase was dried over Na2SO4 and concentrated in vacuo to give an oil (1.4 g) which was purified on a silica gel column using CH2Cl2 as eluant. Pooling of fractions containing the major slower running component afforded the title compound as a colourless solid (0.74 g), m.p. 60.5°-62° C. (from n-pentane/diethyl ether).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29](O)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][NH:33][CH3:34]>>[CH3:32][N:33]([CH3:34])[C:29](=[O:30])[CH2:28][C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: CNC
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 1 of Example 13) and dimethylamine.
Reaction SMILES: C([N:8]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH:9]2[NH:8][CH2:17][CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]2=3)=[CH:21][CH:22]=1
Reactant: COc1ccc(CCC2c3cccnc3C=CN2Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CCC2NCCc3ncccc32)cc1
Reaction time: 4 h
Yield: 93.6 %

Procedure:
To a solution of 2.1 g (5.85 mmol) 6-benzyl-5-[2-(4-methoxy-phenyl)-ethyl]-5,6-dihydro-[1,6]naphthyridine in 70 mL methanol and 7 mL acetic acid was added 210 mg Pd/C 10% and hydrogenated at atmospheric pressure for 4 h at 55° C. The apparatus was purged with argon, the catalyst was filtered and the filtrate was concentrated in vacuo. The oil was dissolved in ethyl acetate and the solution was washed once with a sat. NaHCO3 solution. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to yield 1.47 g (93%) of the title compound was yielded as yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22](C4C=CC=CC=4)[CH3:23])[C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)=[O:4].N.ClCCl.[CH3:35][OH:36]>>[CH2:35]([O:36][C:14]1[CH:15]=[CH:16][C:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][Cl:1])=[CH:12][CH:11]=4)[NH:30][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:23][CH:13]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCl)cc3)cc12)c1ccccc1
Agent: N
Solvent: ClCCl
Product: O=C(CCl)NCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3[nH]2)cc1

Procedure:
This compound is synthesized using an analogous sequence as described for 2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide (steps 40.4 to 40.6); Rf (dichloromethane/methanol/conc. ammonia 90:10:1)=0.40; MS-ES+: (M+H)+=498.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[CH:9][CH:8]=1
Reactant: NCCCO
Reactant: Fc1ccc(CCl)cc1
Product: OCCCNCc1ccc(F)cc1
Yield: 63.9 %

Procedure:
In a similar manner to Reference Example 23, 3-amino-1-propanol (52.0 g) was reacted with 4-fluorobenzylchloride (10.0 g) to obtain 3-(4-fluorobenzylamino)-1-propanol (8.10 g, 64%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of [4-(6-nitropyridin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.089 g, 0.23 mmol) in 1:1 THF:MeOH (5 mL) was added 10% Pd/C (0.051 g). The resulting mixture was stirred under hydrogen atmosphere at 25° C. for 4 h. After filtering through a celite cake, the solution was concentrated in vacuo and yielded the title compound as a light yellow solid (0.039 g, 49% yield). MS (ES+) m/z 351.3.
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[NH:14][C:13](=O)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:18])=O>>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([Cl:18])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reaction time: 3 h

Procedure:
(R)-2-(1-Butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 3.00 g, 16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stirred for 3 h. Excess phosphorus oxychloride was removed under vacuum and the resulting oil was partitioned between dichloromethane and saturated aqueous sodium carbonate. The layers were separated and the organic layer was washed once with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an orange oil, 3.19 g (85%). 1H NMR (CDCl3, 300 MHz) δ 0.98 (t, 3H), 1.54 (d, 3H), 1.67 (m, 2H), 2.48 (t, 2H), 5.68 (q, 1H), 6.36 (d, 1H), 8.21 (d, 1H); [α]D+27.6 (c 1.0, MeOH).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.O>C(Cl)Cl.C(Cl)(Cl)Cl>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][CH:2]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 88 %

Procedure:
N-(6-aminohexyl)-5-nitroisobenzothiazol-3-one hydrochloride was synthesized as follows. A solution of 2.2 g (10 mmol) of 2-chloro-5-nitrobenzoyl chloride in 25 mL of CH2Cl2 was added dropwise to a mixture of 6-t-butoxycarbonylamino-1-hexylamine hydrochloride (Stahl, et al. J. Org. Chem., 43, 2285 (1978)). (2.5 g, 10 mmol) and triethylamine (2.0 g, 10 mmol) in 125 mL of CH2Cl2. After stirring overnight, 150 mL of H2O and 100 mL of CHCl3 were added. The organic phase was separated and the aqueous phase extracted three times with 100 mL of CHCl3. The combined organic extracts were dried (Na2SO4), filtered and the filtrate concentrated to yield 3.5 g (88%) of N-(6-t-butoxycarbonylamino-1-hexyl)-5-nitrobenzamide as a white solid, mp 157°-159° C.