Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC[C@H](NCCCC1C=CC=CC=1)C(N)=O)(=O)C.Cl.C(OC[C@H](NC1CC2C(=CC=CC=2)C1)C(N)=O)(=O)C.Cl.[C:42]([O:50][CH2:51][C@H:52]([NH:56][CH:57]1[CH2:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58]1)[C:53]([NH2:55])=[O:54])(=[O:49])[C:43]1[CH:48]=CC=C[CH:44]=1>CO>[ClH:1].[CH2:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:65][CH:57]1[NH:56][C@@H:52]([CH2:51][O:50][C:42](=[O:49])[CH:43]([CH3:44])[CH3:48])[C:53]([NH2:55])=[O:54]
Reactant: NC(=O)[C@H](COC(=O)c1ccccc1)NC1Cc2ccccc2C1
Agent: CC(=O)OC[C@H](NC1Cc2ccccc2C1)C(N)=O
Agent: CC(=O)OC[C@H](NCCCc1ccccc1)C(N)=O
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)OC[C@H](NC1Cc2ccccc2C1)C(N)=O

Procedure:
With a similar procedure as described in the example 11 the following compounds were prepared: (S)-3-acetyloxy-2-(3-phenylpropylamino)propanamide hydrochloride (CHF 3023.01; compound n. 45); (S)-3-acetyloxy-2-(2-indanylamino)propanamide hydrochloride (CHF 3519.01; compound n. 74); [α]589 (c=1, methanol)=+29.8 (S)-3-benzoyloxy-2-(2-indanylamino)propanamide hydrochloride (CHF 3548.01; compound n. 78)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6](F)[CH:5]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:15](=[CH:14][N:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[N:18]([CH:19]([CH3:21])[CH3:20])[C:6]=2[CH:5]=1
Reactant: CC(C)NC(=O)c1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1c(=O)c2cnccc2c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a suspension of sodium hydride (79 mg, 3.28 mmol) in THF (8 mL) at 0° C. was added a solution of 4-(4-chloro-2-fluorophenyl)-N-isopropylnicotinamide (480 mg, 1.640 mmol) in THF (10 mL) dropwise over a period of 10 min. The reaction mixture was stirred at 0° C. for 1 h and then warmed to room temperature and stirred for an additional 1 h. The reaction mixture was then treated with ice and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (1×5 mL), dried (Na2SO4) and concentrated under reduced pressure to afford crude 8-chloro-6-isopropylbenzo[c][2,7]naphthyridin-5(6H)-one (250 mg, 0.917 mmol, 56% yield). LC/MS (ESI) m/e 273.0 [(M+H)+, calcd for C15H14ClN2O 273.1]; LC/MS retention time (method C): tR=1.98 min; 1H NMR (400 MHz, CDCl3) δ ppm 9.67 (s, 1H), 8.70 (d, J=6.0 Hz, 1H), 8.17-8.19 (d, J=8.4 Hz, 1H), 7.92-7.94 (d, J=5.6 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.26-7.31 (dd, J=8.8, 2.0 Hz, 1H), 3.21-3.28 (m, 1H), 1.71 (d, J=6.8 Hz, 6H).
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:9]1[CH2:12][CH:11]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:10]1)([CH3:8])[CH3:7].[OH-:28].[Na+]>>[C:16]1([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:11]2[CH2:12][N:9]([CH:6]([CH3:8])[CH3:7])[CH2:10]2)[C:14]([NH2:15])=[O:28])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [OH-]
Reactant: CC(C)N1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N1CC(C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C

Procedure:
To 80 ml. of concentrated sulfuric acid preheated to 70° C. was added 25 g. (0.86 mole) of α-(1-isopropyl-3-azetidinyl)-α,α-diphenylacetonitrile at a rate to maintain a temperature of 65°-75° C. The solution was heated at 70° C. for 18 hrs. and poured on ice. The mixture was made basic with 50% sodium hydroxide (while cooling with ice) and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized from ethyl acetate-ethanol to give 15.7 g. (59%) of product melting at 181°-184° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:24])[C@H:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][C@H:5]([OH:24])[C@H:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CN
Yield: 95.5 %

Procedure:
The resultant compound from Example 8 (107 mg, 0.313 mmol) and 10% palladium on carbon (110 mg) in methanol (10 mL) were stirred under a hydrogen atmosphere for 18 hours. The mixture was filtered and evaporated to afford 94.6 mg (96%) of the desired compound. Mass spectrum: (M+H)+ =317.
Reaction SMILES: [Si](O[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]#[N:19])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)=O>C(#N)C>[Br:27][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]#[N:19])=[CH:12][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CC(C#N)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CC#N
Product: N#CC(Cc1ccc(CBr)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
To a cooled (0° C.) solution of 1.5 g (4.27 mmol) of the product of Step C dissolved in 20 mL of acetonitrile, was added 2.12 g (6.4 mmol) of carbon tetrabromide, and 1.68 g (6.40 mmol) of triphenylphosphine. The reaction mixture was stirred 30 minutes at 0° C., then allowed to warm to room temperature and 0.5 mL (6.4 mmol) of acetone was added. The reaction mixture was stirred an additional 16 hours at room temperature, then filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.575 g (45%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:1][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([N:33]3[CH2:34][CH2:35][N:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:38]3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)CC1

Procedure:
The title compound was prepared from N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide and ethyl 2-(4-{[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}-1-piperazinyl)acetate in substantially the same manner, as described in Example 50. The product was obtained as a light yellow solid; mp: 91-92° C.; 1H NMR (400 MHz, DMSO-d6): δ 1.08-1.17 (t, 3H), 1.49-1.56 (m, 2H), 2.02-2.07 (m, 2H), 2.45-2.50 (m, 4H), 2.52-56 (m, 2H), 2.74-80 (m, 2H), 2.86-3.01 (m, 5H), 3.20 (s, 2H), 3.24-3.36 (m, 4H), 3.96-3.99 (d, 2H), 4.01-4.07 (q, 2H), 4.69-4.71 (m, 1H), 6.86-6.88 (d, 2H), 7.05-7.09 (m, 3H), 7.23-7.24 (m, 1), 7.47-7.50 (d, 2H), 8.20 (brs, 4H); MS m/z 640 (M+H)+; Analysis for C28H41N5O8S2×1.0 F3CCO2H×0.18 CH2Cl2 Calc'd: C, 47.13; H, 5.55; N, 9.11; Found: C, 47.02; H, 5.75; N, 8.67.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][CH3:15])[NH:12][C:11](=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@H:9]1[CH2:10][C:11](=[O:16])[N:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)[C@H:13]1[CH2:14][CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (470 mg), 4-bromo-2-chlorobenzonitrile (477 mg), cesium carbonate (944 mg), tris(dibenzylideneacetone)dipalladium(0) (88.5 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (224 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 550 mg, 75%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:36])[CH:21]([O:33][CH2:34][CH3:35])[C:22]([NH:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[O:23])[C:15]2[CH:37]=[CH:38][CH:39]=[CH:40][C:14]=2[C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]1=2)C1C=CC=CC=1.FC(F)(C(F)(F)F)CN>>[CH2:34]([O:33][CH:21]([C:22]([NH:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:28])[F:29])=[O:23])[C:20]([NH:19][C@@H:16]1[C:17](=[O:18])[N:11]([CH2:10][CH2:9][OH:8])[C:12]2[CH:44]=[CH:43][CH:42]=[CH:41][C:13]=2[C:14]2[CH:40]=[CH:39][CH:38]=[CH:37][C:15]1=2)=[O:36])[CH3:35]
Reactant: CCOC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Agent: NCC(F)(F)C(F)(F)F
Product: CCOC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCO)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-ethoxy-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 3. White solid (83%). MS: m/e=530(M+H+).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>C(Cl)Cl.CCCCCC>[Cl:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC=C1CCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C1CCC=C1CCCCCCCCl
Reaction time: 8 h

Procedure:
The following procedure was adopted from H. Hayaski et al., J. Amer. Chem. Soc., 95, 8749 (1972): To a solution containing 643 mg (3.28 mmol) of 2-(7-hydroxyheptyl)-2-cyclopentenone in 0.47 ml carbon tetrachloride at 35° (temperature of the external water bath), under argon, was added, dropwise over 1 hour, a solution containing 860 mg (3.28 mmol) triphenylphosphine in 3 ml of anhydrous methylene chloride. The yellow solution was stirred for an additional 4.0 hours at ca. 35° and overnight at reflux. The resultant brown residue was taken up in hot hexane and filtered through a sintered glass funnel containing a pad of Celite whereupon the filtrate was reduced in volume and column chromatographed using an 80% silicic acid-20% Celite column and benzene to 80% benzene-20% ethyl acetate in a gradient elution (5 ml fractions). Thus 2-(7-chloroheptyl)-2-cyclopentenone was obtained (20.2 mg) as a pale orange oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([C:18]2[N:23]=[C:22]([N:24]3[C@@H:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][O:26][C:25]3=[O:32])[CH:21]=[CH:20][N:19]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C(=O)(O)[O-].[Na+].N#N>O1CCOCC1.CCOC(C)=O>[CH:29]([C@H:28]1[CH2:27][O:26][C:25](=[O:32])[N:24]1[C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)=[CH:3][CH:4]=2)[CH3:9])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:23]=1)([CH3:31])[CH3:30]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(Br)cc2)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(-c3cnn(C)c3)cc2)n1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
In a 5 mL microwave vial a solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamate (101 mg, 0.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.24 mmol), Sodium bicarbonate (0.2 mL, 0.4 mmol, 2 M aqueous solution) in Dioxane (2 mL) was bubbled N2 for 3 min then Cl2Pd(dppf)CH2Cl2 (16 mg, 0.02 mmol) was added. The capped tube was heated to 100° C. for 16 h. After cooling the reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated. The crude material was purified through silica gel column chromatography (EtOAc in Heptane 12 to 100%) to give a white solid (50 mg, 49.3% yield).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH3:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([C:35](O)=[O:36])=[C:20]([CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[CH2:32][CH2:33][CH3:34])[S:21][C:15]=2[N:14]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:13]1=[O:42].Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:56][NH:57][O:58][CH3:59]>ClCCl.C(N(CC)CC)C>[CH3:59][O:58][N:57]([CH3:56])[C:35]([C:19]1[C:16]2[C:17](=[O:18])[N:12]([CH3:11])[C:13](=[O:42])[N:14]([CH2:38][CH:39]([CH3:40])[CH3:41])[C:15]=2[S:21][C:20]=1[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:32][CH2:33][CH3:34])=[O:36]
Reactant: CCCc1nc2ccccc2n1Cc1sc2c(c1C(=O)O)c(=O)n(C)c(=O)n2CC(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2ccccc2n1Cc1sc2c(c1C(=O)N(C)OC)c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 0.08 h

Procedure:
1-Hydroxybenzotriazole (0.14 g) was added to a solution of the product of step b) (0.25 g) in dichloromethane (5 ml). After stirring for 5 minutes, 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride (0.21 g) was added. After stirring for 10 minutes, N,O-dimethylhydroxylamine hydrochloride (0.1 g) and triethylamine (0.15 ml) were added The reaction mixture was stirred for 12 h at room temperature. The solution was concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient of 0-3% methanol in dichloromethane to give the title compound as a yellow solid (0.118 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:8])[C:6]=1[NH2:7].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:8])[C:6]=1[NH:7][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1ncc(Br)c1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(Br)c1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazol-5-amine (500 mg, 2.84 mmol) and pyridine (0.270 ml, 3.41 mmol) in tetrahydrofuran (9.5 ml) was added 2,2,2-trichloroethyl chloroformate (0.472 ml, 3.41 mmol) with ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 289 mg (28.9%) of the desired product as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reaction time: 8 h

Procedure:
3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole (2.7 g, Step A) was dissolved in MeOH (50 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (150 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford 3-(1-methyl-4-piperidyl)indole-5-ylamine as a yellow oil. MS: 230 (M+1). Calc'd. for C14H19N3—229.32.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:7])[CH:6]=1.[F:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]=[O:23])[CH:17]=[CH:18][C:19]=1[CH3:20]>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([NH:1][C:2]2[N:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:7])[CH:6]=2)=[O:23])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(N=C=O)cc1F
Reactant: CCOC(=O)c1nc(N)cn1C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC(=O)Nc2ccc(C)c(F)c2)cn1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.30 g (3.84 mmol) of ethyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (synthesis analogous to Example 4A, stage 3, or else according to Tetrahedron Lett. 2003, 44, 1607 and literature cited therein) are mixed in 50 ml of THF with 1.16 g (7.68 mmol) of 3-fluoro-4-methylphenyl isocyanate under argon and stirred at room temperature overnight. The reaction mixture is filtered, and the filtrate is concentrated in vacuo and purified by preparative HPLC. The residue from filtration affords together with the product obtained after the HPLC purification 715 mg of product.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>C(O)=O>[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:27]([NH:29][CH:3]=[O:4])[CH3:28])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(N)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=CO
Product: CC(CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)NC=O

Procedure:
3-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-1-methylpropylamine trifluoroacetate (115 mg, 0.28 mmol) was reacted with formic acid and 1,1′-carbonyldiimidazole in analogy to example 44. Yield: 46 mg (51%), M+H+: 329.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([NH:8][CH:9]=[N:10][C:11](=[O:28])[O:12][N:13]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-])=O)[CH:15]=1)=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([NH:8][CH:9]=[N:10][C:11](=[O:28])[O:12][N:13]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([NH2:21])[CH:15]=1)=[O:7]
Reactant: COc1cc(C(=O)NC=NC(=O)ON(c2ccc(C)c([N+](=O)[O-])c2)C(C)(C)C)cc(OC)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)NC=NC(=O)ON(c2ccc(C)c(N)c2)C(C)(C)C)cc(OC)c1OC
Reaction time: 10 h
Yield: 73.3 %

Procedure:
In a bottle, a mixture of Boc nitro-guanidine (4) (1.22 g, 2.5 mmol) in MeOH (80 mL) and Pd/C 10% (100 mg) is stirred under H2 at 50 psi for 10 hours. The starting substrate has disappeared; the catalyst is filtered and the solvent is evacuated under vacuum. The residue is purified by column chromatography, eluting with Hept/EtOAc mixture: 7/3, obtaining the title compound as yellow oil (5) (840 mg, 73%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][C:11]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]1=2.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][C:11]2[CH:15]=[C:16]([NH:19][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])[CH:17]=[CH:18][C:10]1=2
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCCC1CCN1CCSc2cc(N)ccc21
Agent: I
Solvent: CCO
Product: CN1CCCC1CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
A suspension of 4-(2-(1-methylpyrrolidin-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.7 g, 2.52 mmol) and methyl thiophene-2-carbimidothioate hydroiodide (1.439 g, 5.05 mmol) in dry ethanol (15 mL) was stirred at room temperature overnight (16 hours) under an argon atmosphere. At this time, the solvent was evaporated, and the residue was partitioned between saturated NaHCO3 solution (50 mL) and dichloromethane (25 mL). The mixture was transferred to a separatory funnel, and the organic layer was removed. The aqueous layer was extracted into dichloromethane (2×25 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was subjected to column chromatography on silica gel (sequence of eluents: 2:98 methanol:dichloromethane, 5:95 methanol:dichloromethane, and 5:95 (2M ammonia in methanol):dichloromethane) to give compound 13 as yellow syrup (0.48 g, 49%). 1H-NMR (DMSO-d6) δ 7.69 (brd, J=2.7 Hz, 1H), 7.57 (brd, J=4.5 Hz, 1H), 7.07 (dd, J=3.9, 4.8 Hz, 1H), 6.52 (dd, J=1.8, 8.1 Hz, 2H), 6.47 (brd, J=1.8 Hz, 1H), 6.38 (brs, 2H), 3.51-3.47 (m, 2H), 3.28-3.22 (m, 2H), 3.05-3.02 (m, 2H), 2.99-2.93 (m, 1H), 2.24 (s, 3H), 2.12-2.06 (m, 2H), 1.94-1.87 (m, 2H), 1.68-1.63 (m, 2H), 1.51-1.42 (m, 2H); ESI-MS (m/z, %): 387 (MH+, 90), 276 (100), 194 (50).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH2:7][NH2:8].CC1[O:11]C=CC=1C(OC)=O.C[O-].[Na+]>C(N)=O>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:8])=[O:11]
Reactant: Cc1occc1CN
Reactant: COC(=O)c1ccoc1C
Agent: C[O-]
Agent: [Na+]
Solvent: NC=O
Product: Cc1occc1C(N)=O
Temperature: 0 °C
Yield: 83 %

Procedure:
(2-Methylfuran-3-yl)methanamine: A solution of 10 mmol (1.256 ml) of methyl 2-methylfuran-3-carboxylate and 38.9 mmol (2.1 g) of NaOMe in 20 ml of formamide was stirred at 100° C. for 30 min. The reaction mixture was poured into ice-water (20 ml) and extracted with ethyl acetate (3×). The extract was dried over MgSO4 and concentrated to give 1.05 g (83%) of 2-methylfuran-3-carboxamide as oil (m/e=126.2 [M+1]). The amide was dissolved in dry THF (10 ml) and drop-wise added to 15 ml of 1M LiAlH4 with 15 ml THF at 0° C. under argon. Then the mixture was stirred for 5 hrs at 60° C. Following cooling, 50% aqueous THF (30 ml) was added to the mixture at 5-10° C. The resulting precipitate was removed by filtration and the filtered solution was dried and concentrated to give an oily product (0.93 g, 84%).