Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][N:6]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1nnc(Cc2ccccc2Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1nnc(Cc2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 14 %

Procedure:
5-(2-Chloro-benzyl)-[1,3,4]thiadiazol-2-ylamine (23 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (21 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (5.7 mg, 0.014 mmol, 14%). ESI-MS m/z calc. 413.1. found; 414.3 (M+1)+ Retention time 3.38 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:59][CH2:58][C:57]([F:61])([F:60])[F:56])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and 2,2,2-trifluoroethylamine (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (37 mg, 50%) which was obtained as a white solid. MS: m/e=410.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:17]C[CH:15]1[CH2:14][NH:13][CH2:12]2.C(N(CC)CC)C>O1CCOCC1>[CH:15]12[CH2:17][CH:11]1[CH2:12][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:14]2
Reactant: C1CC2CNCC12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CC3CC3C2)nc1
Temperature: 65 °C
Yield: 97.5 %

Procedure:
A mixture of 0.5 g (3.15 mmol) of 2-chloro-5-nitropyridine, 0.452 g (3.78 mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and 1.32 mL (6.94 mmol) of triethylamine in 10 mL of dioxane, is heated at 65° C. for 4 h. The reaction mixture is then poured into 50 mL of ice water. The mixture is stirred until the ice has melted completely, then a yellow precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 0.63 g of the expected product in the form of a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[Cl:32])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[O:40](C(C)=O)[C:41]([CH3:43])=O>>[C:41]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[Cl:32])[CH:5]=[CH:4][N:3]=1)(=[O:40])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-3-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (120 mg, 0.27 mmol) in (Ac)2O (5 mL) was added Et3N (0.4 mL, 1.12 mmol). The reaction mixture was stirred at rt for 8 hours and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a white solid (65 mg, 49%).
Reaction SMILES: [C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:38]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([C@@H:53]([O:64][C:65]([C@H:67]3[NH:71][CH2:70][CH2:69][S:68]3)=[O:66])[CH2:54][C:55]3[C:60]([Cl:61])=[CH:59][N+:58]([O-:62])=[CH:57][C:56]=3[Cl:63])[CH:46]=[CH:47][C:48]=2[O:49][CH:50]([F:52])[F:51])[CH2:40][CH2:39]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:38]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([C@@H:53]([O:64][C:65]([C@H:67]3[N:71]([C:17](=[O:18])[C:16]4[CH:20]=[CH:21][C:13]([CH2:12][O:11][C:10]5[CH:22]=[CH:23][CH:24]=[C:8]([C@H:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[NH:25][C:26]([O:28][C@@H:29]6[CH:34]7[CH2:33][CH2:32][N:31]([CH2:36][CH2:35]7)[CH2:30]6)=[O:27])[CH:9]=5)=[CH:14][CH:15]=4)[CH2:70][CH2:69][S:68]3)=[O:66])[CH2:54][C:55]3[C:60]([Cl:61])=[CH:59][N+:58]([O-:62])=[CH:57][C:56]=3[Cl:63])[CH:46]=[CH:47][C:48]=2[O:49][CH:50]([F:52])[F:51])[CH2:40][CH2:39]1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)N3CCS[C@H]3C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)cc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a stirred solution of 4-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoic acid (I17, 61 mg, 0.125 mmol) in DMF (2 mL) was added [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-thiazolidine-2-carboxylate hydrochloride (I5, 71 mg, 0.125 mmol) followed by DMAP (8 mg, 0.06 mmol) and EDC.HCl (48 mg, 0.25 mmol). The mixture was allowed to stir at room temperature for 18 h and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (43 mg, 34%). 1H NMR (400 MHz, DMSO): δ 8.57 (s, 2 H), 8.23 (d, J=9.4 Hz, 1 H), 7.58-7.42 (m, 4 H), 7.37-6.87 (m, 12 H), 7.10 (t, J=74.4 Hz, 1 H), 6.08-5.97 (m, 1 H), 5.84 (d, J=9.1 Hz, 1 H), 5.58-5.48 (m, 1 H), 5.16 (s, 2 H), 4.60-4.53 (m, 1 H), 4.00-3.88 (m, 1 H), 3.88 (d, J=7.0 Hz, 2 H), 3.83-3.73 (m, 1 H), 3.55-2.92 (m, 5 H), 2.79-2.31 (m, 5 H), 1.93-1.13 (m, 6 H), 0.58-0.52 (m, 2 H), 0.32-0.26 (m, 2 H). LCMS (Method 1): [MH+]=1003 at 3.16 min.
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CO.ClC(Cl)(Cl)[C:22]#[N:23]>C(Cl)Cl>[C:22](#[N:23])[C:7]1[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: Nc1ccccc1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccccc1N
Yield: 46 %

Procedure:
To 2 ml of a solution of 2M of boron trichloride in methylene chloride were added a solution of 0.93 g of aniline in 10 ml of methylene chloride, 1.2 ml of trichloroacetonitrile and 1.2 ml of stannic chloride under ice-cooling. The mixture was refluxed on an oil bath for 24 hr. and poured into a mixture of 16 g of potassium carbonate and 32 ml of methanol under ice-cooling. The mixture was refluxed on an oil bath for 1 hr., filtered to remove the insoluble material and evaporated under reduced pressure. The residue was mixed with water and extracted with ether. The ether layer was washed with dilute HCl, dried over anhydrous magnesium sulfate and evaporated. The residue was purified on a Lobar column. The eluate with 5% ethyl acetate-methylene chloride was evaporated and the residue was recrystallized from ether-petroleum ether to give 0.538 g of anthranilonitrile as crystals melting at 48°-50° C.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1.[CH3:14]I>>[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:13][CH3:14])([CH3:11])[CH3:12])[N:9]=1
Reactant: CC(C)(O)c1coc(CCl)n1
Reactant: CI
Agent: N#N
Product: COC(C)(C)c1coc(CCl)n1
Temperature: 40 °C
Reaction time: 26 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(2-(chloromethyl)oxazol-4-yl)propan-2-ol (200 mg, 1.14 mmol) in MeI (3.5 mL) was treated with Ag2O (396 mg, 1.71 mmol) and the resulting mixture (protected from light) was stirred for 26 h at 40° C. The reaction mixture was filtered and the MeI was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a colorless oil: TLC: rf (7:3 hept-EA)=0.33. LC-MS-conditions 06: tR=0.64 min, [M+H]+=190.17.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:6]([N:9]1[CH2:14][CH2:13][N:12]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:11][CH2:10]1)(=[O:8])[CH3:7]
Reactant: CC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(S(=O)(=O)Cl)CC1
Reaction time: 6 h

Procedure:
A solution of sulfuryl chloride (3.55 ml) in chloroform (45 ml) was added a solution of 1-acetylpiperazine (5.66 mg) and triethylamine (6.16 ml) in chloroform (15 ml) dropwise under cooling on an ice-water bath. After stirring for 6 hours, a precipitate was collected by filtration. After drying over sodium hydroxide, 1-acetylpiperazine-4-sulfonyl chloride (2.43 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[CH:16]=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=2[CH:16]=[O:17])=[C:21]([F:28])[CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)Nc1nccc(Br)c1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Temperature: 85 °C
Yield: 51.5 %

Procedure:
To a stirred suspension of tert-butyl (4-bromo-3-formylpyridin-2-yl)carbamate (100 mg, 0.332 mmol), (4-chloro-2-fluorophenyl)boronic acid (57.9 mg, 0.332 mmol) and cesium carbonate (216 mg, 0.664 mmol) in THF (50 mL) and water (8 ml) was added Pd(PPh3)4 (19.19 mg, 0.017 mmol) and the reaction mixture was heated to 85° C. overnight. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (1×25 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (ethyl acetate/hexanes) to afford tert-butyl 4-(4-chloro-2-fluorophenyl)-3-formylpyridin-2-ylcarbamate (60 mg, 0.171 mmol, 35% yield). LCMS (ESI) m/e 349.2 [(M−H)−, calcd for C17H15ClFN2O3 349.1]; LC/MS retention time (Method C): tR=2.05 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:2]=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)=[N:5][CH:6]=1)#[N:9]
Reactant: CCCCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
5.7 G. of 4-chloro-5-cyano-2-(4-n-hexylphenyl)-pyrimidine are reacted in 250 ml. of 50% dioxane with 21.9 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-hexylphenyl)-pyrimidine as colorless crystals having a melting point of 86.3°-87.8° C. (smectic); nematic at 101.3° C; clearing point 102.6°-103.2° c. The substance is identical with the compound obtained according to Example 10.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[N:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)[C@H:2]([NH:1][C:18]2[N:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=2)[CH2:3][C@@H:4]1[CH3:16])(=[O:15])[CH3:14]
Reactant: N#Cc1cnc(Cl)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Temperature: 200 °C
Yield: 89 %

Procedure:
1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 1) (50 mg, 0.177 mmol), 5-chloropyrazine-2-carbonitrile (37.0 mg, 0.265 mmol) and DIPEA (0.123 mL, 0.706 mmol) were combined in NMP (1.5 mL) and heated in a sealed flask under microwave irradiation to 200° C. for 1 h. The mixture was partitioned between water (150 mL) and EtOAc (4×100 mL). The organic layers were combined, washed with brine (2×100 mL), dried by passing through a hydrophobic frit, and concentrated in vacuo. The resulting residue was purified by chromatography (25 g column, EtOAc/cyclohexane gradient) to give 5-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile (61 mg, 0.158 mmol, 89% yield) as a brown gum.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[CH2:9]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CO>[CH2:9]([O:16][C:17]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of trans-4-aminocyclohexanol (35.5 g, 306.6 mmol) in methanol (621 mL) at 0° C. under nitrogen was added N-(benzyloxycarbonyloxy)succinimide (72.8 g, 291.9 mmol). The reaction mixture was slowly warmed to room temperature and after 1 d, poured into 0.25 M aqueous hydrochloric acid solution (2.13 L). The resulting slurry was stirred vigorously for 1 h and then filtered. The filtered solid was washed with water to obtain the title compound (65.65 g, 90%) as a white solid. 13C NMR (400 MHz, (CD3)2SO) δ 155.3, 137.2, 128.3, 127.7, 127.6, 68.1, 65.0, 49.1, 33.9, 30.3. 1H NMR (400 MHz, (CD3)2SO) δ 7.29 (m, 5H), 7.10 (d, J=7.9 Hz, 1H), 4.96 (d, J=2.3 Hz, 2H), 4.76 (d, J=4.0 Hz, 1H), 3.29 (s, 1H), 3.17 (br s, 1H), 1.71 (m, 4H), 1.22 (t, J=9.7 Hz, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15](OC)=[O:16])[N+:11]([O-:19])=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH:9]=2)[CH2:3]1.C(Cl)Cl.[OH-].[Na+]>O>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[N:11]3[O:19][C:15](=[O:16])[N:14]=[C:12]3[N:13]=2)[CH2:3]1
Reactant: COC(=O)Nc1cc(N2CCCC(O)C2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCCC(O)C2)nc2nc(=O)on12
Reaction time: 1 h

Procedure:
5.6 G. of dimethyl racemic-6-(3-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide are suspended in 100 ml. of methylene chloride and 100 ml. of water. The suspension is adjusted with concentrated sodium hydroxide to pH 12.7. The mixture is stirred for 1 hour, the two phases are then separated and the aqueous phase is adjusted to pH 3 with concentrated hydrochloric acid, a white precipitate separating out. This precipitate is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure methyl racemic-5-(3-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 244°-247° C. (decomposition).
Reaction SMILES: [ClH:1].N[C:3]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH2:10][CH3:11])[N:4]=1.N([O-])=O.[Na+]>Cl.[Cu]Cl>[Cl:1][C:3]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH2:10][CH3:11])[N:4]=1
Reactant: Cl
Reactant: CCn1cc(C#N)c(N)n1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CCn1cc(C#N)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.00 g (7.34 mmol) of 3-amino-1-ethyl-1H-pyrazole-4-carbonitrile hydrochloride was dissolved in semi-concentrated hydrochloric acid (50 ml), the mixture was cooled to 0° C. and sodium nitrite (532 mg, 7.71 mmol) was added. The mixture formed was stirred at 0° C. for 45 minutes and then added dropwise to a solution, pre-heated to 60° C., of copper(I) chloride (727 mg, 7.34 mmol) in semiconcentrated hydrochloric acid, with evolution of gas. The reaction mixture was stirred at 60° C. for 2 hours, cooled to RT and extracted with CH2Cl2 (3×50 ml). The combined organic phases were dried over Na2SO4, the solvent was removed and the residue was chromatographed on silica gel using the mobile phase dichloromethane/methanol. This gave 630 mg (55%) of 3-chloro-1-ethyl-1H-pyrazole-4-carbonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([O-])=O>[Pd].C(O)C>[N:13]1([C:5]2[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(N)c1N1CCCCC1
Reaction time: 40 h
Yield: 73.4 %

Procedure:
A mixture of 1-(2,6-dinitro-phenyl)-piperidine (2.31 g) and palladium on carbon (10%, 230 mg) in ethanol (80 mL) was stirred under hydrogen atmosphere (1 atm.), at room temperature, for 40 hours. The catalyst was filtered off on a CELITE™ pad. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (hexane/EtOAc, 80/20) to afford 1.29 g of 2-piperidin-1-yl-benzene-1,3-diamine as an orange solid without further purifications.
Reaction SMILES: NC1N=C2[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][N:5]2C(=O)C=1N=O.C(OC)(=[O:22])C(C)C.C(N)CN>>[C:14]([NH:13][CH2:12][CH2:11][NH2:5])(=[O:22])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CN1CCn2c1nc(N)c(N=O)c2=O
Reactant: COC(=O)C(C)C
Solvent: NCCN
Product: CC(C)C(=O)NCCN

Procedure:
7-AMINO-2,3-DIHYDRO-1-(2-METHYLPROPYL)-6-NITROSOIMIDAZO[1,2-a]PYRIMIDIN-5(1H)-ONE.- Methyl isobutyrate and ethylenediamine in a molar ratio of 1:3 were heated in a closed pressure vessel at 100° for 62 hrs. The mixture was cooled, clarified by filtration, and the excess ethylenediamine removed from the filtrate by distillation in vacuo. The residue was distilled, boiling point 115°-117°/0.9 mm Hg to yield N-isobutyrylethylenediamine whose identity was confirmed by examination of the NMR and IR spectra. The latter, 15 g., was suspended in 200 ml. of dry THF and a solution of 20 g. (ca. 0.5 mole) of lithium aluminum hydride in 200 ml. of dry THF was added dropwise. The mixture was refluxed for 23 hrs., the excess lithium aluminum hydride destroyed by hydrolysis. The insoluble material was removed by filtration, and the filtrate concentrated in vacuo to yield N-(2-methylpropyl)ethylenediamine as an oil, yield 37 g. The identity of the product was confirmed by examination of the NMR spectrum, and 5.8 g. (0.05 mole) thereof was then dissolved in 20 ml. of MeOH and a solution of 5.8 g. (0.055 mole) of cyanogen bromide in MeOH was added in dropwise fashion with cooling. The mixture was stirred for 1/2 hr. and then concentrated in vacuo to an oil. The latter was dissolved in methylene chloride and again concentrated in vacuo to aid in removal of last traces of MeOH. The NMR spectrum of the residue, an oil, confirmed the structure 1-(2-methylpropyl)-1H-imidazo-2-amine hydrobromide. This material was then condensed with ethyl oximinocyanoacetate substantially according to the method described in Procedure 1. The product was recovered by distillation of the solvent from the reaction mixture in vacuo. The residue was dissolved in water and acidified with acetic acid. The precipitate that formed was collected and air dried. The damp solid was recrystallized from methanol/ethanol, m.p. 242.5°-243.5° d.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([C:21](OC)=[O:22])=[C:16]([CH3:25])[C:15]=3[CH:26]=2)=[O:9])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21][OH:22])=[C:16]([CH3:25])[C:15]=3[CH:26]=2)=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)C1=C(C)c2cc(NC(=O)c3ccc(F)cn3)ccc2CCC1
Agent: CC(C)C[AlH]CC(C)C
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(F)cn3)cc21

Procedure:
In a manner similar to the procedure of step 3B, (E)-methyl 2-(5-fluoropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step 43A was reduced with DIBAL to afford the titled compound of Step 43B. LCMS (M+H)+=327.2. 1H NMR (500 HMz, chloroform-d) δ 9.79 (s, 1H), 8.44 (d, J=2.7 Hz, 1H), 8.35-8.31 (m, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.61-7.56 (m, 1H), 7.54 (dd, J=8.1, 2.3 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 4.38 (s, 2H), 2.53 (t, J=7.0 Hz, 2H), 2.13 (s, 3H), 2.09 (quin, J=7.1 Hz, 2H), 2.02-1.95 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[Cl:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][Cl:22])[CH:25]=1
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.8 %

Procedure:
Triethylamine (1.93 mL; 13.78 mmol) was added at 0° C. to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.3 g; 5.51 mmol) and 3-(chloromethyl)benzoyl chloride (1.13 g; 5.79 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 1.45 g (76%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide as a white solid.