Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[Br:12][C:13]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>C1COCC1>[Br:12][C:13]1[CH:21]=[CH:20][C:19]([S:22]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)(=[O:24])=[O:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(S(=O)(=O)n2ccc3ccccc32)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a cooled (20° C.) suspension of sodium hydride (6.59 grams, 164.74 mmol) in 20 mL of THF, was added solution of indole (6.24 grams, 53.33 mmol in 25 mL tetrahydrofuran), slowly over a period of 10 minutes, maintaining mass temperature at 25° C. under nitrogen atmosphere. The mass was diluted with tetrahydrofuran (20 mL). The reaction mixture was further stirred for 1 hour at the same temperature. Then added a solution of 2-bromo-5-chlorosulfonyl benzoic acid (20.01 grams, 66.81 mmol) in tetrahydrofuran (30 mL) slowly over a period of 10 minutes., The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was quenched onto 600 mL cold Water. The reaction mass was acidified with conc. hydrochloric acid to pH 2 and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine solution (2×50 mL), water (2×100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 17.81 grams technical product. The material was used as such in the next step, with out further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[CH:18]([O:21]C)(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:17])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH:9]=1)[CH:18]=[O:21])[C:4]([F:6])([F:5])[F:7]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Yield: 90.9 %

Procedure:
To a stirred and ice-cooled solution of Compound 8 (650 mg, 2.5 mmol) in dry CH2Cl2 (15 ml) was added neat TiCl4 (950 mg, 5.0 mmol) followed by Cl2CHOMe (600 mg, 5.0 mmol). After the addition was complete, the mixture was stirred at room temperature for 5 hr, poured into H2O (60 ml), and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give a yellow oil, which was purified by a column chromatography on silica gel to give Compound 9 (650 mg, 90%)
Reaction SMILES: C([Cl:4])(=O)C.C(O)C.[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:23]=1>C(OCC)C>[ClH:4].[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH:23]=1
Reactant: CC(=O)Cl
Agent: Fc1cccc2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c12
Solvent: CCO
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add dropwise acetyl chloride (2.3 ml, 32.4 mmol) to anhydrous ethanol (50 mL) and stir the solution for 10 min at ambient temperature and add to a solution N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine (10.7 g, 29.2 mmol) in diethyl ether. Concentrate the resulting solution under reduced pressure to give a yellow solid. Recrystallize the yellow solid from ethyl acetate/methanol to give the title compound: mp 163-164° C.; MS (m/e): 367 (M−1), 365 (M−1); Calculated for C19H18F4N2O HCl: Calcd: C, 56.65; H, 4.75; N, 6.95. Found: C, 56.45; H, 4.54; N, 6.90.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].O.[CH3:14][N:15](C)[CH:16]=[O:17]>>[C:1]1(=[O:11])[N:5]([CH:1]2[CH2:2][CH2:10][C:9]3[CH:8]=[CH:7][CH:3]=[CH:4][C:14]=3[NH:15][C:16]2=[O:17])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Product: O=C1Nc2ccccc2CCC1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
80 g of the product which was obtained above were suspended in 140 ml of dimethylformamide. A solution of 72.6 g of potassium phthalimide in 205 ml of dimethylformamide was added to the suspension and the mixture was then stirred at 60° C. for 16 hours. For the working-up, it was cooled down to room temperature and 800 ml of water were slowly added dropwise; the mixture was then stirred for 2 hours while cooling with ice. The resulting crystal slurry was filtered out with suction, washed firstly with a water/dimethylformamide mixture and then with methyl tert-butyl ether, and subsequently dried at 60° C. for 2 days under reduced pressure. 73.3 g of 4,5-dihydro-3-phthalimido-1H-1-benzazepin-2 (3H) -one were obtained with a melting range of from 185° to 195° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)[Cl:23].Cl>C(O)C>[ClH:23].[CH3:1][C:2]1[CH:9]=[CH:8][C:5]2[C:6]([NH2:7])=[N:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc(C#N)c(Nc2ccccc2[N+](=O)[O-])c1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
Combine 4-methyl-2-(2-nitro-phenylamino)-benzonitrile (2.46 g, 9.71 mmol), tin(II) chloride dihydrate (6.57 g, 29.71 mmol), 5N HCl (40 ml), and ethanol (40.0 ml). and stir the mixture at reflux. After 8 hours, cool to ambient temperature. Allow the mixture to stand at ambient temperature overnight and chill for an additional 3 hours in the refrigerator. Remove the resulting precipitate by vacuum filtration and dry it under vacuum to give 1.24 g (49%) of the desired compound as a yellow solid: mass spectrum (ion spray): m/z=224.0 (M+1).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.[NH:13]([C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([O:25][CH3:26])[N:18]=[C:17]([CH3:27])[N:16]=1)[NH2:14]>C(O)(=O)C>[CH3:26][O:25][C:19]1[N:18]=[C:17]([CH3:27])[N:16]=[C:15]([N:13]=[N:14][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[OH:12])[C:20]=1[C:21]([F:24])([F:23])[F:22]
Reactant: COc1nc(C)nc(NN)c1C(F)(F)F
Reactant: O=C1C=Cc2ccccc2C1=O
Solvent: CC(=O)O
Product: COc1nc(C)nc(N=Nc2ccc3ccccc3c2O)c1C(F)(F)F
Temperature: 110 °C

Procedure:
Then, a flask was loaded with acetic acid (50 ml) and 1,2-naphthoquinone (2.9 g), and the temperature was raised up to 110° C. with stirring to dissolve 1,2-naphthoquinone. To this mixture, 4-hydrazino-6-methoxy-2-methyl-5-(trifluoromethyl)pyrimidine (4 g) was added in 30 minutes. After stirring at 110° C. for 3 hours, the heating was stopped and left to cool. The reaction mixture was filtrated. The filtrated crystals were recrystallized with dioxane to give crystals, which were then filtrated and dried to give intended crystals (2.3 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:15]([N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](Cl)=[O:20])[CH:16]=[CH2:17].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH2:15]([N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](=[O:20])[O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=1)[CH:16]=[CH2:17]
Reactant: C=CCN(Cc1ccccc1)C(=O)Cl
Reactant: COC(COc1ccc(O)cc1)OC
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: C=CCN(Cc1ccccc1)C(=O)Oc1ccc(OCC(OC)OC)cc1
Temperature: 25 °C

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole), N-allyl-N-benzylcarbamoyl chloride (0.08 mole), triethylamine (0.05 mole) and xylene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is stirred and heated at reflux for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then washed with water and dried over anhydrous magnesium sulfate. The dried solution is then filtered and stripped of solvent and unreacted starting materials to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-allyl-N-benzylcarbamate as the residue.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH3:47][CH2:48][CH:49]([C:52]1[S:53][CH:54]=[C:55]([C:57](O)=[O:58])[N:56]=1)[CH2:50][CH3:51].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:57]([C:55]3[N:56]=[C:52]([CH:49]([CH2:50][CH3:51])[CH2:48][CH3:47])[S:53][CH:54]=3)=[O:58])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CCC(CC)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CC)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 2-(pentan-3-yl)thiazole-4-carboxylic acid (example 71, step d) (0.081 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and then evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound a as clear gum. Yield 0.25 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](O)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:12]1([C:18](=[S:21])[NH:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[S:21][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:19][N:20]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: NNC(=S)c1ccccc1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)s1
Reaction time: 2 h
Yield: 43 %

Procedure:
3-amino-6-bromo-pyrazine-2-carboxylic acid (1.000 g, 4.588 mmol) and benzenecarbothiohydrazide (759.1 mg, 4.588 mmol) were suspended in acetonitrile (25.00 mL), cooled in an ice bath and then treated with dibromo-triphenyl-phosphorane (4.453 g, 10.55 mmol) The reaction mixture was allowed to stir in an ice bath for 2 hours and then DIPEA (1.778 g, 2.396 mL, 13.76 mmol) was added slowly at 10° C. The reaction was left to stir at 0-10° C. for a further hour and the resultant precipitate was isolated by filtration, washed with a small amount of acetonitrile and dried (659 mg, 43% Yield). MS (ES+) 335.93
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[Na].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)=O>O1CCCC1>[C:12]1([CH2:11][O:18][C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C=O
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1

Procedure:
To a solution of 6-aminocaproic acid (15 g, 0.114 mole) in a 5% aqueous solution of sodium hydroge carbonate (500 ml) and tetrahydrofuran (100 ml), was added benzylchloroformate (19.52 ml, 0.137 mole) dropwise over a 10 minute period. The reaction was allowed to stir at room temperature until carbon dioxide had ceased to eliminate (~24 hours). The reaction was concentrated in vacuo to remove tetrahydrofuran and the aqueous layer was extracted with ethyl acetate and concentrated again to remove organic residue and then acidified to pH 3 and extracted with ethyl acetate (4×), dried over anhydrous magnesium sulfate and concentrated to yield a clear oil. The product was crystallized from ethyl acetate:hexane (1:1). The white solid was recrystallized twice to yield 22.5 g of the title A compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C(O)(=O)C.[C:47](=[O:52])([O:50]C)[O:48][CH3:49]>>[CH3:42][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:35])[CH3:36])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])=[CH:16][C@H:15]4[O:52][C:47]([O:48][CH3:49])=[O:50])[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: COC(=O)OC
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]12C
Solvent: CC(=O)O
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
In 10 ml of dimethyl carbonate was dissolved 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregn-6-en-5α-ol, followed by addition of 0.2 ml of acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 120 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:17][C:18]([C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1)=[O:19])C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][C:22]3[S:23][CH:24]=[C:20]([C:18]([OH:19])=[O:17])[N:21]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)c1csc(CBr)n1
Product: Cc1ccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)cc1

Procedure:
2-(4′-Methyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 4′-methyl-biphenyl-4-ol (purchased from Maybridge plc, Tintagel, Cornwall, UK or from Intermediate 5) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (intermediate 3). Yield: 70 mg. Mass spectrum (ES) MH+=326.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH2:21][C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O.C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:22])/[C:21](=[CH:39]/[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=5)/[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2C1
Reactant: O=Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2/C1=C\c1ccccn1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
1-(4-Fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6 (1H)-one (114, R1=4-Fluorophenyl) (15.0 g, 50.8 mmol) and THF (430 mL) were stirred until a solution formed. The mixture was cooled to about −70° C. then LiHMDS (1M in THF, 53 mL, 53.0 mmol) was added keeping the internal temperature between about −65 and −70° C. After about 45 min picolinaldehyde (16.32 g, 152 mmol) was added. After about 5 min the mixture was allowed to warm to about −10° C. over about 90 min. Acetic acid (5.8 mL, 102 mmol) was added to the mixture then the slurry was concentrated under reduced pressure. The material was partitioned between water (500 mL), sat. aq. NaHCO3 (˜75 mL) and DCM (200 mL). The aqueous layer was extracted with DCM (60 mL) then the combined organics were dried over MgSO4, filtered and concentrated on the rotovap to yield (E)-1-(4-fluorophenyl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one which was used directly in the next step without further manipulation; LC/MS, method 3, Rt=2.46 min, MS m/z 385 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Cl)n1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A solution of 6-chloro-2-pyridinamine (13.776 g, 107 mmol) in toluene (100 ml) and triethylamine (16.28 ml, 118 mmol) at 50° C. under argon was treated with 2,2-dimethylpropanoyl chloride (13.81 ml, 112 mmol). The reaction was then stirred at 50° C. for 4 h and then at rt for 18 h. 2M HCl (200 ml) was then added and the mixture was extracted with diethyl ether (3×500 ml). The organic extracts were dried (MgSO4), filtered and evaporated to give the product as a brown solid (21.005 g, 92%).
Reaction SMILES: [Na:1].[C:2]([C:5]1([O:11][CH2:10]1)[CH2:6][C:7]([O-:9])=[O:8])(=[O:4])[NH2:3].[C-:12]#[N:13].[Na+]>>[Na:1].[C:2]([C:5]([OH:11])([CH2:10][C:12]#[N:13])[CH2:6][C:7]([O-:9])=[O:8])(=[O:4])[NH2:3]
Reactant: NC(=O)C1(CC(=O)[O-])CO1
Reactant: [C-]#N
Agent: [Na+]
Agent: [Na]
Product: N#CCC(O)(CC(=O)[O-])C(N)=O
Reaction time: 4 h

Procedure:
To this solution of sodium-3-carbamoyl-3,4-epoxybutyrate was added a 5 molal aqueous solution of NaCN in proportions of 3 mols per mol of sodium-3-carbamoyl-3,4-epoxybutyrate. The system was agitated for about 4 hours at 35°-40°C. The yield to sodium-3-carbamoyl-3-hydroxy-4-cyanobutyrate was virtually quantitative as determined by NMR.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([O:11][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
To a solution of 1-benzyl-3-tritylglycerol (17.5 g, 0.41 mol) in anhydrous dichloromethane (200 mL) at 0° C. was added triethylamine (8 mL, 0.58 mol) followed by methanesulfonyl chloride (4.1 mL, 0.54 mol). The reaction was stirred at 0° C. for 1 hour, then at room temperature for 2 hours. The reaction mixture was washed with 1N hydrochloric acid (30 mL), dried (Na2SO4), filtered and concentrated. Crystallisation using diisopropyl ether gave the title compound (15.2 g, 72%) as a solid. m/z not found, r.t.=4.41 mins. NMR (400 MHz; CDCl3) δ7.43-7.41 (6H, m), 7.38-7.23 (14H, m), 4.90-4.83 (1H, m), 4.52 (2H, m), 3.75-3.63 (2H, m), 3.41-3.33 (2H, m), 3.02 (3H, s).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].C(O)(=O)C.[BH4-].[Na+]>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(OC)OC)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(OC)OC)c2c1

Procedure:
To a stirred solution of methyl 3-cyclohexyl-1-(2,2-dimethoxyethyl)-2-(2-formylphenyl)-1H-indole-6-carboxylate (0.16 M, 1 eq, from Step 2) and 2-dimethylaminoethylamine (2 eq) in THF was added glacial acetic acid to adjust the pH of the reaction to ca. pH 4. The reaction was stirred for 1 h after which the THF was removed under reduced pressure and the residue redissolved in MeOH. NaBH4 (8 eq) was added portionwise until complete conversion was observed by LC-MS analysis. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted into EtOAc (×3). The combined organics were washed with H2O and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained as a pale yellow oil and taken on without further purification (quantitative); MS (ES+) m/z 522 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.[O:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:29]([CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CN(C2CCOCC2)c2nc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (6.6 g, 15.8 mmol) and diisopropylethylamine (4.0 g, 31.6 mmol) in acetonitrile (50 mL) was added tetrahydro-2H-pyran-4-amine (6.4 g, 63.2 mmol) and the mixture was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue which was purified by chromatography on silica gel (5-20% ethyl acetate in petroleum ether) to give the title compound (1.98 g, 40% yield). MS (ESI) m/z 313.1 [M+1]+.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.[Cl:29]C1C=C(CS)C=CC=1>>[Cl:29][C:7]1[CH:2]=[C:3]([CH2:9][S:10][C:13]2[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]3[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=3[N:14]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: SCc1cccc(Cl)c1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc2[nH]c(=O)cnc12
Yield: 35.9 %

Procedure:
The titled compound (66 mg) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.20 g) and 3-chloro-benzenemethanethiol (92 mg).