Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][NH:30][CH3:31]>CN(C)C=O>[CH3:29][N:30]([CH3:31])[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(N(C)C)cc1)N(C)C
Reaction time: 24 h

Procedure:
A stirred autoclave is filled with 50 g (0.167 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzylbutan-1-one (crude product from B), 300 ml of dimethylformamide and 23.1 g (0.167 mol) of potassium carbonate. 22.6 g (0.5 mol) of dimethylamine are then added under pressure (3-4 bar). The mixture is heated to 100° and stirred at this temperature for 24 hours.
Reaction SMILES: [S:1]1[CH2:12][C:11](=O)[NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][C:3](=O)[CH2:2]1.B#B.Cl.[OH-].[Na+]>C1COCC1>[S:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C1CSCC(=O)NCCNCCN1
Agent: B#B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C1CNCCSCCNCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Thia-4,7,10-triazacyclododecane-3,11-dione (8.10 g, 37.3 mmol) was suspended in dry THF (distilled from lithium aluminium hydride) (2000 ml) and refluxed under nitrogen for 8 hours with continuous addition of freshly generated diborane (approx. 0.4 mol in total). The reaction mixture was cooled to ambient temperature, 6N HCl (80 ml) was added, and the mixture was stirred for 1 hour. Sodium hydroxide (20 g, 0.5 mol) was added and the solution was evaporated to dryness. The residue was extracted with ethanol (3×50 ml), the extracts were concentrated and 1-thia-4,7,10-triazacyclododecane was purified by extraction (acetonitrile) and sublimation (Kugelrohr). Yield 3.73 g (53%), white solid, m.p. 51°-54° C. (uncorrected). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=3)=[CH:21][S:22][C:13]=12.[CH3:31][NH:32][CH3:33].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[C:20]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][N:32]([CH3:33])[CH3:31])=[CH:27][CH:28]=3)=[CH:21][S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3c(-c4ccc(C=O)cc4)csc23)c(Cl)cc1Cl
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Nc2c(C#N)cnc3c(-c4ccc(CN(C)C)cc4)csc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-3-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.44 mmol) and 1.1 mL of a 2 M solution of dimethylamine in tetrahydrofuran (2.20 mmol) in 5 mL of dichloromethane and 1 mL of dimethylformamide is cooled to 0° C. Sodium triacetoxyborohydride (560 mg, 2.64 mmol) is added in portions followed by 3 drops of acetic acid. The resulting mixture is stirred at room temperature for 2.5 hours then quenched by the addition of water. The mixture is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of methanol in dichloromethane to provide 147 mg (69%) of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-3-{4-[(dimethylamino)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 201–202° C.; 1 H NMR (DMSO-d6) δ 2.19 (s, 6H), 3.46 (s, 2H), 3.86 (s, 3H), 7.38 (d, J=8 Hz, 2H), 7.42 (s, 1H), 7.78 (s, 1H), 7.89 (d, J=8 Hz, 2H), 8.31 (s, 1H), 8.69 (s, 1H), 9.78 (s, 1H); MS 483.0, 485.0 (M+H)+; HRMS found: 483.08061 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CNC1CCCCC1NC>[Cu]I.O.CCO>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:24]=[N+:25]=[N-:26])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(Br)c2)COC1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(N=[N+]=[N-])c2)COC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of [5-(3-bromo-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (114 mg, 0.295 mmol), NaN3 (77 mg, 1.18 mmol), CuI (11 mg, 0.059 mmol), sodium ascorbate (12 mg, 0.059 mmol), N,N′-dimethyl-cyclohexane-1,2-diamine (13 mg, 0.089 mmol), 1.5 ml of EtOH and 0.6 ml of water was stirred under N2 at 90° C. for 1 h. The mixture was filtered through Celite, and the filtrate was chromatographed on silica gel (cyclohexane/EtOAc=6:1) to yield the title compound in the form of a colourless foam. TLC (hexane/EtOAc=3:1): Rf=0.33; HPLC: RtH1=2.258 min; 1H-NMR (400 MHz, CDCl3); 7.40-6.88 (m, 4H; broad signals due to rotamers), 4.75-3.60 (m, 6H), 1.42 (br, 9H); MS: 350 [(M+H)+].
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:7][CH2:8][CH3:9].[C:19](=[O:21])=[O:20].CCOCC>C1COCC1>[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([F:18])[C:14]([C:19]([OH:21])=[O:20])=[C:15]([F:17])[CH:16]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1cc(F)cc(F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCOc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.5M in hexane; 3.60 ml, 0.038 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 16 (7.00 g, 0.038 mol) in dry THF (35 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured onto a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide which was then acidified with 36% hydrochloric acid. The product was filtered off and dried (CaCl2) in vacuo to give a colourless solid.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O:22][N:23]1[CH2:27][C@H:26]([CH2:28][CH3:29])[C@H:25]([NH:30]CC2C=CC(OC)=CC=2)[C:24]1=[O:40])C1C=CC=CC=1>ClCCl.O>[NH2:30][C@H:25]1[C@@H:26]([CH2:28][CH3:29])[CH2:27][N:23]([OH:22])[C:24]1=[O:40]
Reactant: CC[C@H]1CN(OCc2ccccc2)C(=O)[C@H]1NCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC[C@H]1CN(O)C(=O)[C@H]1N
Reaction time: 2 h
Yield: 44.1 %

Procedure:
Dichlorodicyanobenzoquinone (125 mg, 550 μmol) was added to a stirred solution of cis-1-benzyloxy-4-ethyl-3-(4-methoxybenzylamino) pyrrolidin-2-one (190 mg, 458 μmol) in dichloromethane (20 ml) and water (1 ml). After 90 min the mixture was evaporated, dissolved in dilute hydrochloric acid, and applied to a column containing DOWEX 50W-X8 (100-200 mesh, 2×2 cm, H+ form). After washing the column with water (100 ml), the product was eluted with dilute aqueous ammonia. Fractions containing the product were evaporated in vacuo, then purified by flash chromatography, eluting with dichloromethane: methanol (95:5 v/v). The resulting oil (62 mg) was hydrogenated on palladium black (30 mg) in ethanol (20 ml) and acetic acid (200 μl) at 50 p.s.i. for 2 h. After filtration and evaporation, the residue was dissolved in water and applied to a column containing DOWEX 50W-X8 (100-200 mesh, 2× 2 cm, H+ form) After washing the column with water (50 ml), the product was eluted with dilute aqueous ammonia. Fractions containing the desired product were freeze dried to give cis-3-amino-1-hydroxy-4-ethylpyrrolidin- 2-one (29.1 mg, 45%) as a white powder. 1H NMR (360 MHZ, D2O) δ3.82 (1 H, d, J=8.0 Hz, CHN), 3.69 (1 H, dd, J=7.3 and 10.0 Hz, NCHAHB), 3.38 (1 H , dd, J=4.8 and 10 0 Hz, NCHAHB), 2.45-2.55 (1 H, m, CHCH2), 1.5-1.6 and 1.3-1.4 (2 H, m, CH2CH3), 0.96 (3 H, t, J=7.3 Hz, CH3), m/z (CI, NH3) 145 (M+ +H).
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:21][CH:20]=[N:19][CH:18]=1)CCC.O1CCOCC1>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.[Cu](I)I.CN(C=O)C>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[S:21][CH:20]=[N:19][CH:18]=1)([O-:9])=[O:8]
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1csc([N+](=O)[O-])c1-c1cncs1
Temperature: 110 °C
Yield: 61.4 %

Procedure:
A microwave vial equipped with a stir bar was added 4-bromo-5-nitrothiophene-3-carbonitrile (0.24 g, 1.05 mmole) and tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), copper iodide (0.028 g, 0.15 mmol) and then purged with N2 (g) inlet prior to addition of 5-(tributylstannyl)thiazole (0.63 g, 1.67 mmol), dioxane (2.3 mL) and few drops of DMF. The reaction mixture was heated at 110° C. for 30 min and then concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 5-nitro-4-(thiazol-5-yl)thiophene-3-carbonitrile (153 mgs, 61%) Retention time (min)=1.715, method [4], MS(ESI) 238.0 (M+H).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([OH:7])[CH2:4][CH2:5][Br:6].N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>CN(C)C=O>[Br:6][CH2:5][CH2:4][C@@H:3]([CH2:2][Br:1])[O:7][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O[C@H](CBr)CCBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](O[C@H](CBr)CCBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of (S)-1,4-dibromo-2-butanol (5.0 g) in N,N-dimethylformamide (30 mL) were added imidazole (1.91 g) and tert-butylchlorodiphenylsilane (7.1 mL) under ice-cooling, followed by stirring the mixture at room temperature for 13 hours. To the reaction mixture were further added imidazole (0.59 g) and tert-butylchlorodiphenylsilane (1.77 mL), followed by stirring the mixture at room temperature for 7 hours To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:50) to give ((S)-3-bromo-1-bromomethyl-propoxy)-tert-butyldiphenylsilane (8.56 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[C:8]#[N:9]>>[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[C:10]([CH3:14])[C:7]=1[C:8]#[N:9]
Reactant: Cc1cccc(Cl)c1C#N
Reactant: O=[N+]([O-])O
Product: Cc1c([N+](=O)[O-])ccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of aqueous 90% nitric acid was cooled to -35° C., and 40.0 grams (0.264 mole) of 2-chloro-6-methylbenzonitrile was added in one portion. The reaction mixture was then allowed to warm to ambient temperature, where it was stirred for about 18 hours. After this time, the reaction mixture was poured into 3000 mL of ice-water. After the ice melted, the resultant solid was collected by filtration and dried. The NMR spectrum of the solid indicated that it was about 75% pure product. The solid was recrystallized twice from methanol, yielding 13.9 grams of 2-chloro-6-methyl-5-nitrobenzonitrile, mp 85.5°-87.5° C. The NMR spectrum was consistent with the proposed structure. The filtrates from the recrystallizations were combined and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding an additional 20.4 grams of 2-chloro-6-methyl-5-nitrobenzonitrile, mp 87.5°-89.5° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].[OH-].[Ca+2].[OH-]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N+:9]([O-:19])[C:8]([C:12]#[N:13])=[CH:7][CH:6]=2
Reactant: Cc1ccc2ccc(C#N)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc2ccc(C#N)[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methylquinoline-2-carbonitrile (14.2 g, 84 mmol) in dichloromethane (400 mL) was added 3-chloroperoxybenzoic acid (50%, 36.4 g, 106 mmol) and stirred at room temperature overnight. Solid calcium hydroxide (7.8 g, 106 mmol) was added and 15 min later the mixture was filtered through celite, rinsed with dichloromethane and the liquors evaporated to dryness to give the crude compound. The compound was purified by flash chromatography on silica gel (eluting with 5% acetone in dichloromethane) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.40 (s, 1H), 8.05 (d, 1H), 7.97 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].[C:25]([NH:32][C@H:33]([CH:38]=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl>O1CCCC1>[CH2:23]([O:22][C:19](=[O:21])[CH2:20][CH:38]([OH:39])[CH:33]([NH:32][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH3:24]
Reactant: CCOC(C)=O
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)CC(O)C(CC(C)C)NC(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
To diisopropylamine (7.7 g, 0.077 mol) in dry tetrahydrofuran (26 mL) cooled to -20 degrees C. under argon was added dropwise n-butyllithium in hexane (1.46 M, 52.4 mL, 0.077 mol). The solution was stirred 15 min, the temperature lowered to -78 degrees C. and dry ethyl acetate (6.7 g, 0.077 mol) added dropwise while maintaining the temperature below -75 degrees C. The solution was stirred 10 min and a precooled (-78 degrees C.) tetrahydrofuran solution of Boc-L-leucinal (11 g, 0.051 mol) was added. After 30 min, 2 M HCl (40 mL) was added and the mixture was slowly warmed to 10 degrees C. and extracted with ether (3 ×200 mL). The combined ethereal extract was washed with saturated sodium chloride and dried with magnesium sulfate and filtered. Evaporation of the filtrate in vacuo gave 14 g of crude product which was purified by flash chromatography (20% ethyl acetate in hexane) to give 6 g of desired product.
Reaction SMILES: [CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([O:61][Si:62]([CH:69]([CH3:71])[CH3:70])([CH:66]([CH3:68])[CH3:67])[CH:63]([CH3:65])[CH3:64])=[C:57]([Cl:72])[CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([O:61][Si:62]([CH:66]([CH3:68])[CH3:67])([CH:69]([CH3:70])[CH3:71])[CH:63]([CH3:65])[CH3:64])=[C:57]([Cl:72])[CH:56]=2)[N:48]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1Cl)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5-c5ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(Cl)c5)c5ccccc54)cn23)CC1)(C(C)C)C(C)C

Procedure:
A solution of Intermediate G (153 mg, 0.28 mmol) and [5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2011/154734A1, which is incorporated herein by reference, 167 mg, 0.28 mmol) in 1,4-dioxane (4 mL) and DIPEA (87 μL, 0.50 mmol) was stirred at 95° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM, to give 1-[5-tert-butyl-2-(3-chloro-4-triisopropylsilanyloxy-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-(4-triisopropylsilanyloxymethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea (193 mg). This was dissolved in THF (3 mL) and treated with TBAF (1M in THF, 0.47 mL, 0.47 mmol). The solution was stirred at RT for 1.75 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-25% [2M NH3 in MeOH] in DCM, to give the product. This was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound (72 mg, 56%). LCMS (Method 5): Rt 3.99 min, m/z 685 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.38-1.52 (2H, m), 1.55-1.66 (1H, m), 1.73-1.96 (4H, m), 1.98-2.17 (2H, m), 2.85-2.97 (2H, m), 3.3-3.5 (4H, m, under water signal), 4.52 (1H, br s), 4.77-4.85 (1H, m), 5.55 (1H, br t, J=4.4 Hz), 6.28 (1H, s), 7.05 (1H, s), 7.08 (1H, s), 7.15 (1H, dd, J=2.0, 9.8 Hz), 7.23-7.40 (5H, m), 7.44 (1H, d, J=2.5 Hz), 7.61 (1H, d, J=9.9 Hz), 7.64 (1H, br d, J=1.5 Hz), 8.02 (1H, br s), 10.55 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Cl)c2ccccc12
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c2ccccc2c1O
Reaction time: 1 h

Procedure:
4-Chloro-1-naphthol, 9 g, in 100 ml acetic acid was cooled to 15° C. and 3.25 ml concentrated nitric acid in 20 ml acetic acid was added dropwise over 15 minutes. After 1 hour, the reaction mixture was poured into 600 ml chilled water. The precipitate was filtered off, washed with water and dried to give a crude product. The product was partially purified by extracting with boiling hexane to obtain 3.5 g. Further purification was accomplished by dissolving in 10 ml chloroform, absorbing on 15 g silica and loading on a column of 90 g silica gel, equilibrated with hexane. The product was eluted with 5% ethyl acetate in hexane to give 0.8 g of 4-chloro-2-nitro-1-naphthol after evaporation, m.p. 142°-3° (d).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=O)[S:8][C:4]=2[CH:3]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:9]([C:7]1[S:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:13]=[CH:12][C:5]=3[CH:6]=1)=[O:11])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2ccc(Br)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1

Procedure:
900.0 mg (3.50 mmol) of 6-bromo-1-benzothiophene-2-carboxylic acid (Example 10A), 697.0 mg (3.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 1597.1 mg (4.20 mmol) of HATU, 1628.7 mg (12.60 mmol) of N,N-diisopropylethylamine and 8.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M hydrogen chloride in dioxane and 1N hydrochloric acid, and the solution is then concentrated. Recrystallization from methanol/ethanol (1:10) affords 594 mg (42% of theory) of the title compound in the form of yellowish-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=[O:23])=[CH:8][CH:9]=1.[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:25]1([O:23][C:22]([C:7]2[CH:6]=[C:5]3[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]4[C:4]3=[CH:3][C:2]([Cl:1])=[C:19]3[C:14]=4[N:15]=[CH:16][CH:17]=[CH:18]3)=[CH:9][CH:8]=2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Reactant: OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OC1CCCC1)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 28.4 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (150 mg, 0.41 mmol), cyclopentanol (0.19 ml, 2.0 mmol), EDC.HCl (88 mg, 0.45 mmol), DMAP (6 mg, 0.04 mmol) and DMF (1 ml) gave the title compound (50 mg, 28%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[N:14]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:13][C@@H:12]([S:28]C(=O)C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][CH2:9][C@H:10]1[N:14]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:16])=[O:17])[CH2:13][C@@H:12]([SH:28])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)S[C@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc2ccccc2c1)N1C[C@@H](S)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.2 %

Procedure:
S-Acetyl deprotection: To a solution of (3S,5S)-thioacetic acid S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl] ester (1.2 g) in methanol (17 ml) was added sodium methanolate (28%-solution in methanol, 0.55 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 h, and acetic acid (0.17 ml) was added. The reaction mixture was concentrated, and the residue was extracted with EtOAc. The organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:3 and 1:2 as eluents to obtain (3S,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol (0.59 g) as a slightly coloured syrup, MS: 414 (MH+).