Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([N:21]([CH:35]([CH3:37])[CH3:36])[C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)=[O:20])[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][C:10]([CH3:39])([CH3:38])[C:9]1=[O:40])=[O:4].[ClH:42].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:42].[F:41][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([N:21]([CH:35]([CH3:36])[CH3:37])[C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)=[O:20])[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][C:10]([CH3:39])([CH3:38])[C:9]1=[O:40])=[O:4]
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCNC(=O)C(F)F)C(=O)C(C)(C)S2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCNC1)N(CCNC(=O)C(F)F)C(=O)C(C)(C)S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-[[(4-{2-[(difluoroacetyl)amino]ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)carbonyl](isopropyl)amino]piperidine-1-carboxylate (1 g) in chloroform (8 ml) was added a 4N hydrochloric acid/dioxane solution (8 ml), and the mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure to give the title compound (0.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: Cc1ccc2cc3ccccc3cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cc3ccccc3cc2c1
Temperature: 25 °C
Yield: 109.2 %

Procedure:
2-Methylanthracene (5.00 g, 26.25 mmol, 1 eq), N-bromosuccinimide (4.70 g, 26.25 mmol, 1 eq), benzoyl peroxide (1.0 g) and carbon tetrachloride (250 mL) were mixed and refluxed for 6 hours. The mixture was cooled to room temperature, and the succinimide precipitate filtered. The filtrate was evaporated to dryness and the residue taken up in ethyl acetate (250 mL) and washed with 1 N NaOH (3×200 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to yield 7.77 g of a light brown solid which was used without purification in the next step. NMR (DMSO-d6): δ 4.90 (s, 2H, CH2Br). ##STR55##
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:11]([OH:14])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1.[OH-].[K+].O>N1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:10][C:9]3[C:4]([C:1](=[O:3])[CH:2]=2)=[CH:5][C:6]([S:11]([OH:14])(=[O:12])=[O:13])=[CH:7][CH:8]=3)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1cc(S(=O)(=O)O)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=O)c3cc(S(=O)(=O)O)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14.3 %

Procedure:
To a solution of 2′-hydroxyacetophenone (5.43 g, 40 mmol) in cyclohexane (28 mL) was added dimethylcarbonate (28 mL). The mixture was stirred under nitrogen and heated to 60° C. Chlorosulfonic acid was added over a period of 15 min. Liberated HCl was removed by trapping with solid NaOH. On completion of the addition, the reaction mixture was heated to 70° C. for 1 h and then cooled to rt. The solid was filtered off, washed with a mixture of dimethyl carbonate and cyclohexane (1:1, 20 mL) and dried under vacuum to give 3-acetyl-4-hydroxybenzene sulfonic acid as yellow solid (4.5 g, 52%). 3-Acetyl-4-hydroxybenzene sulfonic acid (2.16 g, 10 mmol) was suspended in 20 mL anhydrous pyridine. 4-Methoxybenzoyl chloride (3.4 g, 20 mmol) was added slowly at rt. Stirring continued under nitrogen for 15 h. Excess pyridine was removed under reduced pressure. The solid obtained was dried under vacuum. This material was used without further purification. This crude compound (˜10 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered KOH (2.8 g, 50 mmol) was added and the reaction mixture was stirred at rt for 14 h under nitrogen. Water (10 mL) was added and the mixture was concentrated to dryness. The crude product was taken in 10 mL of glacial AcOH. Five drops of concentrated HCl was added and the reaction mixture was stirred at 110° C. for 4 h, then cooled to rt. The yellow solid was isolated by filtration, washed with AcOH and dried under vacuum to give 2-(4-methoxy phenyl)-4-oxo-4H-chromen-6-sulfonic acid (0.475 g, 14%) as yellow solid. The product (0.375 g, 1.13 mmol) was suspended in HI (7 mL). Glacial AcOH (3 mL) was added and the reaction mixture was stirred at 110° C. for 2 h, then cooled to rt. The solid was isolated by filtration, washed with AcOH and dried under vacuum. The crude compound was triturated with ether to afford 2-(4-hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid (0.2 g, 55%) as yellow solid. MS (ES) m/z: 319.88 (M+1), 318.85 (M); 13C-NMR (DMSO-d6): δ 177.5, 163.7, 161.7, 156.1, 146.1, 132.1, 129.1, 123.1, 122.3, 122.2, 118.7, 116.6, 105.5.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([C:13]([C-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1)=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].[OH-].[K+]>C(O)C>[C-:15]1([C:13]([CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([OH:20])=[O:3])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: CCCCCCCC(C(=O)OCC)C(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCC(C(=O)O)C(=O)[c-]1cccc1
Yield: 103.4 %

Procedure:
20.5 g of ferrocenoylnonanic acid ethyl ester prepared in the above (1) and 5.1 g of potassium hydroxide were refluxed in ethanol for 2 hours and then treated with acid to obtain 19.7 g of ferrocenoylnonanic acid of the following formula [7]. ##STR29##
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[NH2:28][C@H:29]([C:34]([NH:36][C@H:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[C@H:30]([CH2:32][CH3:33])[CH3:31].Cl>>[NH2:1][C@H:2]([C:15]([NH:28][C@H:29]([C:34]([NH:36][C@H:37]([C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42])[CH:38]([CH3:39])[CH3:40])=[O:35])[C@H:30]([CH2:32][CH3:33])[CH3:31])=[O:16])[CH2:3][CH2:4][C:5](=[O:6])[OH:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C

Procedure:
37 g of Z-Glu(OBzl)OH are reacted with 32 g of H-Ile-Val-OBut.HCl and the product is worked up, as described in Example 21 (C). After catalytic hydrogenation the compound is a single substance according to chromatography.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[O:12])=[C:5]([CH3:39])[CH:4]=1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:24][CH:25]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[O:12])=[C:5]([CH3:39])[CH:4]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3CCNCC3)cc2)c2ccc(Cl)cc2C)ccn1
Yield: 108 %

Procedure:
Hydrogen chloride solution (4 M in 1,4-dioxane, 0.66 mL, 2.6 mmol) was added to a solution of (R)-tert-butyl 4-(4-(1-(4-chloro-2-methylphenyl)-3-(2-methylpyridin-4-yl)-3-oxopropyl)phenyl)piperidine-1-carboxylate (example 387, step 1; 140 mg, 263 μmol) in ethanol (4 mL) to give a colourless solution, then after 20 h the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to afford the title compound (123 mg), which was used without further purification. Off-white foam, MS (ESI+): m/z=433.1 ([M+H]+).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCCCCc1ccncc1Br
Product: CCCCCCc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 8, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromo-4-hexylpyridine (Intermediate 13), the title compound was obtained as a beige solid after purification by preparative HPLC.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=[C:13]([Cl:21])[CH:12]=1>CCOC(C)=O>[N:1]1([C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=[C:13]([Cl:21])[CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(Cl)cc1-n1nnc2ccccc21
Temperature: 150 °C

Procedure:
A 1:1 mixture of benzotriazole and methyl 4,6-dichloronicotinate was heated neat in a preheated oil bath at 150° C. for a period of 10-15 min. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed successively with saturated NaHCO3 and brine. The organic phase was separated, dried over MgSO4 and filtered. After evaporation of the organic solvent, the isomers in the residue were purified and separated by flash chromatography (10-70% EtOAc in hexanes) to provide the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[N:3]=1.[K].[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[N:29][CH:30]=1)([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH:18]3[CH2:20][CH2:19]3)[N:3]=2)(=[O:33])=[O:32])=[N:29][CH:30]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1Cl
Agent: [K]
Product: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
According to the procedure described in Example 1g) 3.3 g 4,6-dichloro-2-cyclopropyl-5-(o-methoxyphenoxy)-pyrimidine (prepared according to procedures described in Example 1) was reacted with 5-i-propyl-2-pyridyl-sulfonamide potassium salt to give 4.04 g 5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide. LC-MS: tR=5.64 min, [M−1]−=473.29.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[CH3:28][N:29]([CH3:40])[CH2:30][CH2:31][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[SH:39].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:28][N:29]([CH3:40])[CH2:30][CH2:31][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Reactant: CN(C)CCNc1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Yield: 90.5 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (560 mg, 0.87 mmol) was treated with 2-(2-(dimethylamino)ethylamino)benzenethiol (258 mg, 1.31 mmol), potassium carbonate (181 mg, 1.31 mmol) and copper(I) iodide (250 mg, 1.31 mmol) according to the method described in Preparation 44. The crude was purified using SP1® Purification System (0%-100%, hexane-ethyl acetate) to give 432 mg (90% yield) of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#N.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:22]=[CH:23][C:24]=1[CH:25]=[CH:26][C:27]1[S:28]C=[CH:30][CH:31]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.C(Cl)(Cl)Cl>CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:22]=[CH:23][C:24]=1[CH:25]=[CH:26][C:27]1[S:28][C:1]([C:3](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[C:9]#[N:10])=[CH:30][CH:31]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C(C#N)=C(C#N)C#N)s2)c(OCc2ccccc2)c1
Temperature: 40 °C
Yield: 31.7 %

Procedure:
In 3 ml of N,N-dimethylformamide, 0.13 g (1.01 mmol) of tetracyanoethylene was dissolved. With stirring under ice cooling, 0.4 g (0.95 mmol) of [3-benzyloxy-4-[2-(thiophene-2-yl)vinyl]phenyl]dibutyl amine was dissolved in 1 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 40 minutes and further stirred with heating at 40° C. overnight. After the reaction mixture was poured into 100 ml of water, extraction with chloroform, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography and washed with ethanol to give 157 mg of a black crystal having a mp of 125-130° C. (yield: 31.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[N:7]([N:11]([CH3:17])C(=O)OCC)[CH:8]=[CH:9][CH:10]=1)=[O:5].[OH-].[Na+].[CH2:24](O)C>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[N:7]([NH:11][CH3:17])[C:8]([CH3:24])=[CH:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1Cl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CNn1c(C)ccc1C(=O)c1ccccc1Cl

Procedure:
A solution containing [2-(2-chlorobenzoyl)-1H-pyrrol-1-yl]-methyl-carbamic acid, ethyl ester (29.4 g, 91 mmol) and sodium hydroxide (11 g, 275 mmol) in 50% aqueous ethanol was heated under reflux for 16 hours. The excess ethanol was evaporated and the solution was adjusted to pH 7 with 10% HCl. The resultant slurry was extracted with three 100 ml portions of DCM, dried (MgSO4), filtered, and evaporated to give 22 g of solid. This solid was charcoaled and recrystallized from ether-hexane to give 21 g (93%) of powder, m.p. 107°-108°.
Reaction SMILES: [F-].[K+].C[Si](C)(C)[C:5]([F:8])([F:7])[F:6].Br[C:12]1[N:13]=[CH:14][C:15]([N:18]2[C:25]3[C@@H:24]4[CH2:26][C@@H:23]4[CH2:22][C:21]=3[C:20]([C:27]([OH:29])=[O:28])=[N:19]2)=[N:16][CH:17]=1.Cl>[Cu]I.CCOC(C)=O.CN1CCCC1=O>[F:6][C:5]([F:8])([F:7])[C:12]1[N:13]=[CH:14][C:15]([N:18]2[C:25]3[C@@H:24]4[CH2:26][C@@H:23]4[CH2:22][C:21]=3[C:20]([C:27]([OH:29])=[O:28])=[N:19]2)=[N:16][CH:17]=1
Reactant: O=C(O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(O)c1nn(-c2cnc(C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 50 °C
Reaction time: 17 h
Yield: 16.1 %

Procedure:
In an oven-dried 20 mL scintillation vial were placed potassium fluoride (523 mg, 9.00 mmol) and copper (I) iodide (1714 mg, 9.00 mmol). N-Methyl-2-pyrrolidinone (10 mL) was added to the mixture followed by trimethyl(trifluoromethyl)silane (2.66 mL, 18.00 mmol). The reaction was stirred at 50° C. for 1 h. (1aR,5aR)-2-(5-Bromopyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (289 mg, 0.900 mmol) (from Example 1.13, Step B) was then added. The brown mixture was stirred at 50° C. for 17 h before poured into 1 M HCl (75 mL). EtOAc (50 mL) were added and the mixture was stirred vigorously for 5 minutes. The mixture was filtered and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were concentrated and the residue was purified by preparative HPLC to give the title compound as a yellow solid (45 mg). LCMS m/z=311.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+]>C(=O)(OC)OC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COC(=O)OC
Product: CC(C#N)c1ccc(Br)cc1
Yield: 1498.8 %

Procedure:
A solution of 50.0 g (225.0 mmol) of 4-bromophenylacetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.[CH3:16][N:17]=[C:18]=[O:19]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@@H:12]([NH:15][C:18]([NH:17][CH3:16])=[O:19])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: N[C@@H]1CCN(c2cccc3c2CCO3)C1
Solvent: ClCCl
Product: CNC(=O)N[C@@H]1CCN(c2cccc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 497.5 %

Procedure:
(R)-N-(2,3-Dihydrobenzofuran-4-yl)-3-(amino)pyrrolidine (0.1 mmol) was dissolved in CH2Cl2 and methyl isocyanate (0.12 mmol) was added. The reaction was stirred at room temperature for 1 hour. The solvents were removed in vacuo, and the compound purified by flash chromatography eluting with 10% methanol in ethyl acetate to give 130 mg (98%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:20]CCCCCC)[N:18]=[CH:19][N:12]2[N:11]=1)[CH3:2].[S:27]([Cl:31])(Cl)(=[O:29])=[O:28]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:27]([Cl:31])(=[O:29])=[O:28])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:20])[N:18]=[C:19]([CH2:10][CH2:5][CH2:4][CH2:9][CH2:8][CH2:7][CH3:6])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCCCCCc1ncn2nc(-c3ccccc3OCC)[nH]c(=O)c12
Reactant: O=S(=O)(Cl)Cl
Product: CCCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-heptyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (Example 22A). This gives 0.3 g (78.9%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]([OH:30])=O.C(N(C(C)C)CC)(C)C.[OH:40][C:41]([CH3:71])([CH3:70])[CH2:42][C@@:43]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[O:48][C:47](=[O:49])[N:46]([C@H:50]([C:52]2[CH:57]=[CH:56][C:55]([CH:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)[CH3:51])[CH2:45][CH2:44]1>CN(C)C=O>[OH:40][C:41]([CH3:70])([CH3:71])[CH2:42][C@@:43]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[O:48][C:47](=[O:49])[N:46]([C@H:50]([C:52]2[CH:57]=[CH:56][C:55]([CH:58]3[CH2:63][CH2:62][N:61]([C:28]([C@@H:24]4[CH2:25][CH2:26][CH2:27][O:23]4)=[O:30])[CH2:60][CH2:59]3)=[CH:54][CH:53]=2)[CH3:51])[CH2:45][CH2:44]1
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C(O)[C@@H]1CCCO1
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: C[C@@H](c1ccc(C2CCN(C(=O)[C@@H]3CCCO3)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (125 mg) was added to a solution of (S)-tetrahydro-furan-2-carboxylic acid (45 mg) and diisopropylethyl-amine (200 μL) in N,N-dimethylformamide (2 mL) at room temperature. The resulting solution was stirred for 30 min, before (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (150 mg) dissolved in dimethylformamide (1 mL) was added. The resulting solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([O:11][CH2:12][C:13](=[O:38])[C@:14]2([OH:37])[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C@:28]([F:34])([C@@H:29]([OH:33])[CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:35])[CH:24]=[CH:25]3)[CH2:20][CH2:19]4)[CH2:16][C@H:15]2[CH3:36])=[O:10])[CH:4]=1.C([O-])(O)=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO>[F:34][C@:28]12[C@@H:29]([OH:33])[CH2:30][C@@:31]3([CH3:32])[C@@H:17]([CH2:16][C@@H:15]([CH3:36])[C@:14]3([OH:37])[C:13](=[O:38])[CH2:12][O:11][C:9]([C:5]3[CH2:6][CH:7]=[CH:8][N:3]([CH3:2])[CH:4]=3)=[O:10])[C@@H:18]1[CH2:19][CH2:20][C:21]1[C@:26]2([CH3:27])[CH:25]=[CH:24][C:23](=[O:35])[CH:22]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)COC(=O)c1ccc[n+](C)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: CO
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)COC(=O)C1=CN(C)C=CC1

Procedure:
The general reduction procedure of Example 11 of U.S. Pat. No. 4,617,298 was followed, using 0.78 mmol of the steroidal quaternary salt prepared in Example 117, 0.33 g of NaHCO3 and 0.41 g of Na2S2O4 in 50% aqueous methanol at 0° C., with a nitrogen purge. The product had the structural formula: ##STR146##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si](C(C)(C)C)(C)C)=[CH:7][C:6]=1[CH3:19])[CH3:2].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:47]([O:49][C:50](=[O:64])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=1[O:62][CH3:63])[CH3:48].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[CH2:47]([O:49][C:50](=[O:64])[CH2:51][N:52]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=1[O:62][CH3:63])[CH2:19][C:6]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH3:48]
Reactant: CCOC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(O)ccc1C(=O)OCC
Reaction time: 6.5 h
Yield: 43 %

Procedure:
A mixture of 20 g (68 mmol) of 4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-benzoic acid ethyl ester, 12.1 g (68 mmol) of N-bromosuccinimide, 1.5 g (6.8 mmol) of benzoyl peroxide in 230 mL of carbon tetrachloride was heated at reflux temperature for 5 hours. The resultant mixture was cooled, filtered through a plug of silica gel, and concentrated under reduced pressure. To the residue (12.2 g) was added 8.0 g (28.7 mmol) of N-(2,4-dimethoxy-benzyl)glycine ethyl ester, 3.96 g (28.7 mmol) of potassium carbonate, and 65 mL of anhydrous DMF and the mixture was stirred for 6.5 hours. The mixture was then partitioned into a biphasic water-ethyl acetate mixture and the isolated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by flash chromatography: eluting the desired product from silica gel with a gradient of 10-90% ethyl acteate in hexanes. 5.33 g of the title compound (yellow oil) was isolated; MS (ESI+): 432.2 (M+1)