Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:40](O)(=[O:44])[CH:41]([CH3:43])[CH3:42]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)C(=O)O
Reactant: Nc1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
To a stirred solution of 5-Indole amine (0.5 g, 3.78 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimidehydrochloride (1.45 g, 7.56 mmol), 1-hyroxybenzotriazole (0.578 g, 3.78 mmol) in anhydrous DMF (25 mL), triethylamine (1.0 mL, 7.5 mmol) and isobutyric acid (0.31 mL, 3.4 mmol) were added and stirred at room temperature for 12 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resultant residue was purified by flash column chromatography to give N-(1H-indol-5-yl)isobutyramide (0.596 g, 77.8%); MS: 203.1 (M+1)
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:17]4[CH2:18][CH2:19][N:20]=[C:21]([CH3:22])[C:16]4=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>CO.O.C(Cl)Cl.C(O)C>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:17]4[CH2:18][CH2:19][NH:20][CH:21]([CH3:22])[C:16]4=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1=NCCn2c1ccc2-c1ccc(OC2CCCC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC1NCCn2c(-c3ccc(OC4CCCC4)cc3)ccc21
Yield: 66 %

Procedure:
6-[p-(Cyclopentyloxy)phenyl]-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine (1.5 g) was dissolved in a mixture of 100 ml of methanol, 10 ml of water and 25 ml of methylene chloride under argon. The solution was treated portionwise with 0.6 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the solvent was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 60 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.6 g of brown oil, was dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 1.2 g (66%) of 6-[p-(cyclopentyloxy)phenyl]-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (2:1); m.pt.: 172°-174° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].II>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(Br)cc1
Agent: II
Solvent: C1CCOC1
Product: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A cooled (−30° C.) solution of 8-[2-(4-bromo-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.200 g; 3.927 mmol) in anhydrous THF (90 ml) was treated dropwise with a solution of 1-Methylmagnesium bromide in THF (10.25 ml; 10.25 mmol; 2.6 eq.) until complete removal of the iodine substituent. The mixture was then quenched with water (5 ml), diluted with ether (100 ml), and was allowed to warm-up to rt. This solution was washed with brine (2×150 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=15/1) to give the pure product 8-[2-(4-bromo-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (1.570 g; 92%). LC-MS: tR=0.93 min.; [M+H]+=435.98 g/mol.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18][N:17]=[N:16][C:15]=1[NH:27][NH2:28]>C1COCC1>[Cl:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:28][N:27]=2)[N:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of triphosgene (30.4 g, 102.4 mmol) in THF (300 mL), 1-[4-chloro-5-(4-chloro-phenyl)-pyridazin-3-yl]-hydrazine (6.52 g, 25.61 mmol) was added in portions over 15 min at room temperature. The mixture was stirred at room temperature for 4 h. After this time, the solution was poured into ice/water (500 mL), and the resulting light yellow solid was collected by filtration. The solid was rinsed with aqueous 0.5N HCl and water. It was then dried under vacuum to give the title compound, 2.81 g of 8-chloro-7-(4-chlorophenyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one as a light yellow solid. HPLC: 2.78 min; MS, M+H=281.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=1>>[CH3:12][O:13][C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:18]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: COC(=O)CCc1cccc(CNS(=O)(=O)c2ccccc2)c1

Procedure:
The title compound was prepared following the procedure described in Step B of Example 3 from benzenesulfonyl chloride and 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, prepared of Preparation 44. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, 2H), 7.58-7.47 (m, 3H), 7.17 (m, 1H), 7.06 (m, 1H), 6.99 (m, 2H), 4.62 (m, 1H), 4.10 (d, 2H), 3.84 (s, 3H), 2.84 (t, 2H), 2.53 (t, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[CH2:3]1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([O:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[CH2:3]1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: NC(=O)CN1CC(O)CC1=O
Product: CC(=O)OC1CC(=O)N(CC(N)=O)C1

Procedure:
A mixture of 5.53 g 2-(4-hydroxypyrrolidin-2-on-1-yl) acetamide and 44.3 ml acetyl chloride is refluxed for 15 minutes. It is then cooled, the solvent is evaporated in vacuo and the residue oil taken up with a small quantity of aqueous sodium bicarbonate, and solid sodium bicarbonate is added under stirring until neutrality. Most of the water contained in the mixture is removed by treatment in vacuo with methylisobutylketone, the residue is taken up with methylene chloride, made anhydrous over sodium sulphate and evaporated in vacuo. The residue oil is slurried into isopropyl alcohol/ethyl ether and crystallized from isopropyl alcohol/isopropyl ether (20:80) to obtain 2-(4-acetoxypyrrolidin-2-on-1-yl) acetamide, which purified by chromatography melts at 84°-86° C.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>O1CCCC1>[O:3]1[CH2:4][CH2:5][N:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=3[N+:27]([O-:29])=[O:28])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of trans-4-morpholinocyclohexanamine dihydrochloride (5 g, 19.44 mmol), 4-fluoro-3-nitrobenzenesulfonamide (4.32 g, 19.63 mmol) and triethylamine (20 ml, 143 mmol) in tetrahydrofuran (60 ml) was stirred for 16 hours at room temperature. The solid product was filtered off, washed with tetrahydrofuran, ether, dichloromethane (3×) and dried under vacuum.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:14][NH2:15])[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:2]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([C:26]4[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=4)[CH:30]=3)[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: CN1CCC(CN)(c2cccc(-c3ccccc3)c2)CC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2cccc(-c3ccccc3)c2)CC1
Yield: 31 %

Procedure:
This compound was synthesized from (4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 31%) as an off white solid. 1H NMR (400 MHz, MeOD) δ 8.39 (m, 1H), 8.23-8.21 (m, 1H), 7.90-7.88 (m, 1H), 7.64-7.54 (m, 4H), 7.49-7.47 (m, 3H), 7.39-7.36 (m, 2H), 7.31-7.28 (m, 1H), 3.60 (m, 2H), 2.79-2.76 (m, 2H), 2.42-2.30 (m, 4H), 2.23 (m, 3H), 2.11-2.06 (m, 2H). MS (ESI) m/z: Calculated for C29H27F3N4O2: 520.21. found: 521.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:18])[C:3]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cccc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Br)cccc1CBr
Temperature: 80 °C
Yield: 98.6 %

Procedure:
1-Bromo-3-methyl-2-(methyloxy)benzene (30.3 g, 0.15 mol), NBS (28.2 g, 0.16 mol), and BPO (1.83 g, 7.55 mmol) were suspended in 300 mL of CCl4, and the mixture was heated to 80° C. over night. After cooling to room temperature, the solution was filtrated and the solid was washed with CCl4 (30 mL×2). The filtrate was washed with NaHSO3 (aq. 250 mL×2), Na2CO3 (aq. 100 mL×2), brine (100 mL) and dried over Na2SO4. After removing the solvent, 41.4 g of the crude product was obtained (yield: 97.9%).
Reaction SMILES: C([O:3][CH:4]([O:8][CH2:9][CH3:10])N(C)C)C.[CH3:11][C:12]1[N:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2C(O)=O)[N:15]=[N:14][N:13]=1>ClCCl>[CH3:11][C:12]1[N:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[C:4]([O:8][CH2:9][CH3:10])=[O:3])[N:15]=[N:14][N:13]=1
Reactant: Cc1nnnn1-c1cnccc1C(=O)O
Reactant: CCOC(OCC)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccncc1-n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylformamide diethyl acetal (46 mL) was added to a suspension of 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid (36 g) in dichloromethane (800 mL). The reaction mixture was stirred at ambient temperature overnight then washed six times with water (500 mL), dried over magnesium sulfated, and concentrated under vacuum. The residue was recrystallized from ethyl acetate/hexanes to provide 40 g of ethyl 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate as a solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][OH:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(CO)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (59 mg, 73%), MS (ISP) m/z=325.5 [(M+H)+], mp 220° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].[Cl-].[OH:10][NH3+:11].C(N(CC)CC)C>>[OH:10][N:11]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[NH2:8]
Reactant: [NH3+]O
Reactant: N#Cc1ccccn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccccn1

Procedure:
1.0 g (9.6 mmol) of pyridine-2-carbonitrile, 1.0 g (14.4 mmol) of hydroxylammonium chloride and 1.6 ml (11.5 mmol) of triethylamine were reacted according to the General Method 5A. Yield: 1.06 g (80% of theory)
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH2:18])[S:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][CH2:25][C:26]#[C:27][C:28]1[S:32][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:30][C:29]=1[C:39](O)=[O:40]>>[CH3:23][O:24][CH2:25][C:26]#[C:27][C:28]1[S:32][C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:30][C:29]=1[C:39]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:14]1[S:13][C:10]2[C:9]([N:15]=1)=[CH:8][C:7]([CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:12][N:11]=2)=[O:40]
Reactant: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Reactant: COCC#Cc1sc(-c2ccccc2)nc1C(=O)O
Product: COCC#Cc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Yield: 30 %

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 5-(3-methoxyprop-1-ynyl)-2-phenylthiazole-4-carboxylic acid. The product was isolated using workup 2 and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2) followed by recrystallization from MeOH to give the title compound (111 mg, 30% yield). MS Calcd for C31H27N5O2S2: 565.16. Found (M+H)+ m/z=566.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]2)=[CH:11][C:10]=1[CH3:24])C1C=CC=CC=1.C(O)C.[H][H]>[OH-].[OH-].[Pd+2].C1COCC1>[CH3:24][C:10]1[CH:11]=[C:12]([N:15]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1O
Yield: 86.7 %

Procedure:
A mixture of 1-(4-(benzyloxy)-3-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (670 mg, 2.0 mmol), 20% palladium hydroxide on activated carbon (50 mg), ethanol (20 ml), and THF (20 ml) was shaken under 40 psi of hydrogen gas at the ambient temperature for 3 days and at +50° for 1 day, to drive reaction to completion. The reaction was filtered through a pad of Celite and the mother liquor was concentrated to obtain the target product as a colorless solid (420 mg, 86%). MS (M+1): 243.0.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[Na].Br[C:7]1[N:14]=[C:13]([NH2:15])[CH:12]=[C:11]([NH2:16])[C:8]=1[C:9]#[N:10]>O>[NH2:16][C:11]1[C:8]([C:9]#[N:10])=[C:7]([O:4][CH:2]([CH3:3])[CH3:1])[N:14]=[C:13]([NH2:15])[CH:12]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: CC(C)O
Agent: [Na]
Solvent: O
Product: CC(C)Oc1nc(N)cc(N)c1C#N
Temperature: 150 °C
Yield: 53 %

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 6 mL of 2-propanol and 150 mg (6.5 mmol) of sodium. The mixture was stirred at 95° C. until all of the sodium had reacted (15 minutes), then 650 mg (3.05 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 150° C. for 10 minutes then cooled and diluted with 30 mL of water. The precipitate was collected, washed with water until pH=7, then dried under reduced pressure at 95° C. to provide 312 mg (53%) of pale yellow crystals.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14](=[O:15])[CH2:13][C@H:12]1[OH:26].CC(C)=O.C(O)(=O)C>CO>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([OH:27])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C@@H:14]([OH:15])[CH2:13][C@H:12]1[OH:26]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1O

Procedure:
Refer to Chart E wherein E is --CH=CH--, R2 and R4 are methyl, V is ---(CH2)5 --, W is 1-pentyl, and ~ is either alpha or beta. A solution of sodium borohydride (0.6 g.) in 10 ml. of methanol at 0° C. is added to a solution of PGE1, methyl ester, 15-methyl ether (Example 5, 1.5 g.) in 60 ml. of methanol and the mixture is stirred at 0° C. for 30 minutes. Acetone (10 ml.) is added and the solution is made slightly acid with dilute acetic acid in methanol. The mixture is concentrated by evaporation under reduced pressure and the residue is taken up in dichloromethane. The resulting solution is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed over silica gel wet-packed in 8% methanol in dichlormethane ad rinsed with 300 ml. of dichloromethane, eluting with 2-10% methanol-dichloromethane. Those fractions shown by TLC to contain PGF1α , methyl ester, 15-methyl ether free of starting material and impurities are combined and concentrated to yield the Formula -VI PGF1α -type title compound. Likewise, those fractions shown by TLC to contain PGF1β, methyl ester, 15-methyl ether are combined and concentrated to yield the Formula-VI PGF1β -type title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:49]([C:51]1[N:52]=[C:53]([C:64]([O-])=[O:65])[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=1)#[N:50].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:22][C:18]1([CH3:21])[CH2:19][CH2:20][C:15]([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[CH3:23])[CH:13]=[CH:12][C:11]=2[NH:14][C:64]([C:53]2[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=[C:51]([C:49]#[N:50])[N:52]=2)=[O:65])=[CH:16][CH2:17]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 215 mg (0.638 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 446 mg (0.957 mmol) of PyBroP, 214 mg (0.701 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) and 333 μL (1.91 mmol) of DIEA and stirred at RT for 18 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 355 mg (95%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C29H43N5O4SSi, 586.3 (M+H). found 585.9.
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH3:15])[N:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[C:7]([CH3:22])([CH3:21])[CH2:6]1)C.[Cl:23][C:24]1[CH:25]=[C:26]([NH:37][C:38]([NH2:40])=[NH:39])[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[C:26]([NH:37][C:38]2[N:40]=[CH:4][C:5]3[CH2:6][C:7]([CH3:21])([CH3:22])[C:8]4[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][N:11]([CH3:15])[C:12]=4[C:13]=3[N:39]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1nn(C)c2c1C(C)(C)CC(=CN(C)C)C2=O
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2Cl)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(Nc3ccc(N4CCN(C)CC4)c(Cl)c3)nc1-2
Reaction time: 37 h
Yield: 88.2 %

Procedure:
A solution of ethyl 6-[(dimethylamino)methylene]-1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (0.50 g, 1.6 mmol) and N-[3-chloro-4-(4-methylpiperazin-1-yl)-phenyl]-guanidine (0.48 g, 1.8 mmol) in anhydrous dimethylformamide was heated to 100° C. and kept at this temperature for 37 hours. After cooling, the mixture was diluted with water (50 mL) and the resulting precipitate was collected by filtration and dried to give the title compound (0.72 g, 85% yield) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[F:15])[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccccc1C1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2F)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 40% overall yield. FDMS m/e=368 (M+ of free base). α[D]589 =-12.31 (c=0.61, methanol).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]1[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCOCC1>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc2ccccc2n1CCCl
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1-c1nc2ccccc2n1CCN1CCOCC1

Procedure:
0.31 g. of 1-(2-chloroethyl)-2-(5-nitro-1-methyl-2-imidazolyl)-benzimidazole are boiled for 12 hours with 0.18 g. of morpholine in 50 ml. of dioxane. By evaporation and preparative thin-layer chromatography of the mixture, 50 mg. of 1-(2-morpholinoethyl)-2-(5-nitro-1-methyl-2-imidazolyl)-benzimidazole is obtained, the hydrochloride of which has a melting point of 237° C.