Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][C:14]3[C:20]([Br:21])=[C:19](I)[S:18][C:15]=32)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:23][C:24]([Si](C)(C)C)([F:26])[F:25]>CN(C=O)C.CN1CCCC1=O.[Cu]I>[C:3]([O:7][C:8]([N:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][C:14]3[C:20]([Br:21])=[C:19]([C:24]([F:26])([F:25])[F:23])[S:18][C:15]=32)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2Cc3c(sc(I)c3Br)C2C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2Cc3c(sc(C(F)(F)F)c3Br)C2C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Dipyridyl (31 mg, 0.20 mmol), CuI (34 mg, 0.18 mmol) and KF (10 mg, 0.18 mmol) were added to a solution of the product from step b) (78 mg, 0.17 mmol) in 1.6 mL of 1:1 DMF/1-methyl-2-pyrollidinone. The reaction mixture was stirred for 1 hour at 80° C. and then cooled to room temperature. Next, trifluoromethyl trimethylsilane (118 mg, 0.83 mmol) was added and the reaction mixture was heated to 80° C. for 12 hours. The reaction was cooled to room temperature and filtered through a silica plug eluting with CH2Cl2 (10 ml). The organic mixture was washed with brine (2×3 mL), dried with MgSO4, and was concentrated to a dark oil that was purified by preparative LC/MS to give the subtitle compound. MS calculated for C15H17BrF3NO2S +H: 412, observed: 413.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH:11]([NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:40]=[CH:39][C:38]4[C:37]([CH3:42])([CH3:41])[CH2:36][CH2:35][C:34]([CH3:44])([CH3:43])[C:33]=4[CH:32]=3)[N:30]=2)[CH2:22][CH2:21]1)[CH2:12][CH2:13][C:14](OCC)=[O:15])C.O>C1COCC1>[CH3:41][C:37]1([CH3:42])[CH2:36][CH2:35][C:34]([CH3:43])([CH3:44])[C:33]2[CH:32]=[C:31]([C:29]3[N:30]=[C:26]([N:23]4[CH2:24][CH2:25][CH:20]([NH:19][CH:11]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:10][OH:9])[CH2:21][CH2:22]4)[S:27][CH:28]=3)[CH:40]=[CH:39][C:38]1=2
Reactant: CCOC(=O)CCC(NC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC(CO)CCCO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 mg (0.11 mmol) of lithium aluminium hydride were initially introduced in 2 ml of THF, and 21 mg (0.04 mmol) of 2-{1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamino}pentanedioic acid diethyl ester from step a, pre-dissolved in 2 ml of THF, were slowly added. The reaction mixture was stirred at room temperature overnight, 20 ml of water were added, and the mixture was extracted twice with EA. The organic phase was dried over sodium sulfate, filtered, stripped off to dryness and purified by means of preparative HPLC. The product is in the form of the TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]Cl)[CH:5]=[CH:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11]1>>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:14]2[NH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(SCl)c1
Reactant: COC(=O)c1cc[nH]c1
Product: COC(=O)c1c[nH]c(Sc2cccc(F)c2)c1

Procedure:
By the same procedure, m-fluorobenzenesulfenyl chloride is reacted with methyl pyrrole-3-carboxylate to form methyl 5-(3-fluorophenylthio)pyrrole-3-carboxylate.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)C1)=O)(C)(C)C.[C:25]([O:29][C:30]([N:32]1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2C[CH:33]1[CH2:34][CH2:35]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH:10]([C:13]2[NH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:11]2[CH2:12][CH:33]1[CH2:34][CH2:35]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Following the procedure used to prepare compound 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, except that 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was used instead of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>O1CCCC1>[CH2:23]([O:22][CH2:21][C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCCC1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(COCc1ccccc1)(C(=O)OCC)C1CCCCC1
Reaction time: 1 h
Yield: 107.2 %

Procedure:
Diethyl cyclohexylmalonate (18.7 g.) was added to a stirred suspension of sodium hydride (4.8 g. 50% dispersion in oil) in dry tetrahydrofuran (50 ml) under nitrogen. The mixture was refluxed, with stirring, for one hour. The mixture was cooled and benzyl chloromethyl ether (13.9 g.) in dry tetrahydrafuran (50 ml) was added and the mixture was refluxed, with stirring, for three hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. Diethyl 2-benzyloxymethyl-2-cyclohexyl-malonate (30 g.) was obtained as a brown oil and was used without further purification.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:42][CH2:43]OS(C)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:49]=[N+:50]=[N-:51].[Na+].CN(C=O)C>O>[N:49]([CH2:43][CH2:42][C:15]1[N:14]([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:22]2[C:17]([C:16]=1[CH2:24][CH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)=[N+:50]=[N-:51]
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
Ethyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate (1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together under N2 and heated to 60° C. After 1 hour the reaction was cooled and water was added. Extracted with EtOAc/Et2O mix and washed with water and brine and dried over sodium sulfate. Removed solvent to obtain ethyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (light-brown solid) in 96% yield.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]2[N:4]=[CH:5][N:1]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=3)[N:2]=2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: c1cncc(-c2nc[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc(-n2cnc(-c3cccnc3)n2)n1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
100 mg (684 μmol) of 3-(1H-1,2,4-triazol-3-yl)pyridine (preparation cf. J. Org. Chem. 1979, 44, 4160-4164), 124 mg (683 μmol) of 2-chloro-6-(trifluoromethyl)pyridine and 142 mg (1.03 mmol) of potassium carbonate were initially charged in 5 ml of N,N-dimethylformamide, and the mixture was stirred at 120° C. for about 18 hours. After cooling, water was added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. This gave 180 mg (90% of theory) of 2-[3-(pyridin-3-yl)-1H-1,2,4-triazol-1-yl]-6-(trifluoromethyl)pyridine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[O:8])=[CH:5][N:6]=1.[Cl:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([C:21]1SC(N=CN(C)C)=NC=1)=[O:20]>Cl>[NH2:1][C:2]1[S:3][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[O:8])=[CH:5][N:6]=1.[Cl:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19](=[O:20])[CH3:21]
Reactant: CN(C)C=Nc1ncc(C(=O)c2ccccc2Cl)s1
Agent: Cl
Agent: Nc1ncc(C(=O)c2ccccc2Cl)s1
Product: CC(=O)c1ccccc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
(2-Amino-thiazol-5-yl)-(2-chloro-phenyl)-methanone The crude N′-[5-(2-chloro-benzoyl)-thiazol-2-yl]-N,N-dimethyl-formamidine was dissolved in 10% aqueous hydrochloric acid (150 mL) and heated to 70° C. for 4 hours. The precipitate was filtered, washed with ether, and then suspended in a 10% aqueous sodium carbonate solution (250 mL). The suspension was stirred for 1 hour and the precipitate was filtered, washed with ether, and dried in air to give (2-amino-thiazol-5-yl)-(2-chloro-phenyl)-methanone as a brown solid (8.5 g, 36 mmol, 55% from 1-(2-chloro-phenyl)-ethanone). ESI-MS m/z calc. 238.0, found 239.3 (M+1)+ 1H NMR (DMSO): δ: 7.252 (s, 1 H), 7.420-7.553 (m, 4H), 8.345 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7](=O)[C:6](=O)[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.[C:32]([NH2:35])(=[S:34])[CH3:33]>COCCOCCOC>[CH3:33][C:32]1[S:34][C:7]2[CH2:8][CH2:9][C:10]3[C:2]([CH3:16])([CH3:1])[CH:3]([CH3:15])[C:4]([CH3:14])([CH3:13])[C:5]=3[C:6]=2[N:35]=1
Reactant: CC(N)=S
Reactant: CC1C(C)(C)C2=C(C(=O)C(=O)CC2)C1(C)C
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Solvent: COCCOCCOC
Product: Cc1nc2c(s1)CCC1=C2C(C)(C)C(C)C1(C)C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione is first prepared with 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF) via oxidation with (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione (10 g, 0.04 mol), thioacetamide (CH3CSNH2) (3.5 g, 0.04 mol), and diglyme (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Diglyme is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 2,6,6,7,8,8-hexamethyl-5,6,7,8-tetrahydro-4H-3-thia-1-aza-as-indacene (˜10 g) is obtained.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:22]([O:24]C)=O)[C:15](=[CH:20][CH:21]=1)[C:16]([O:18]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:28](OCC)(=O)C>CC(C)=O>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][CH:21]=1)[C:16](=[O:18])[CH2:28][C:22]2=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(OCCCOc2ccccc2)cc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CC(=O)c2cc(OCCCOc3ccccc3)ccc21
Yield: 22 %

Procedure:
A solution of dimethyl 4-(3-phenoxypropoxy)phthalate (13.6g, 0.0395 mole) in ethyl acetate (12 ml) was added to a 50% dispersion of sodium hydride in mineral oil (2.54 g) and the mixture heated at reflux for 4 hrs. After cooling, the mixture was triturated with 50% ethanol, ether and the yellow solid filtered off and added to a hot (70°-80° C.) 10% solution of hydrochloric acid (150 ml). After 2 mins a yellow oily solid separated which was isolated by decantation and taken up in acetone from which it crystallised on concentration to give 2.533g (22%) of material of m.p. 91°-94° C., νmax (mull) 1740, 1710, 1605 cm-1 ; τ(DMSO) 7.78 (2H quintet; J 6.4Hz); 6.68 (2H, s); 5.83 (2H, t, J 6.4Hz); 5.62 (2H, t, J 6.4Hz); 3.21-2.44 (7H, m); 2.12 (1H, m). (Found; C, 72.97; H, 5.61; C18H16O4 requires; C, 72.96; H, 5.44%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(CO)(c2ccc(Cl)cc2)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC1(c2ccc(Cl)cc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 66 %

Procedure:
The 4-hydroxymethyl-4-(4-chlorophenyl)cyclohexanone is dissolved in 60 ml. of pyridine and 30 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness to give 12.8 g. (66% yield) of 4-acetoxymethyl-4-(4-chlorophenyl)cyclohexanone, as an amorphous gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=1)=[O:12].IC.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH3:22])[CH:18]=1)=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(/C=C/c1cc(Cl)ccc1Cl)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)/C=C/c2cc(Cl)ccc2Cl)ccc1=O

Procedure:
In analogy to example 161, step 1, (E)-5-(3-(2,5-dichlorophenyl)acryloyl)pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.C(O)C.C1(C)C=CC(S([CH2:24][N+:25]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:24]#[N:25])[CH2:8]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.1 %

Procedure:
To a solution of 2-adamantanone (6.24 g, 41.50 mmol) in anhydrous 1,2-dimethoxyethane (150 mL) was added anhydrous ethanol (3.6 mL, 61.00 mmol) and p-toluenesulfonylmethyl isocyanide (10.0 g, 51.50 mmol) at 0° C. Potassium tert-butoxide (7.03 g, 62.70 mmol) was added in portions over 35 minutes under nitrogen atmosphere. The reaction mixture was stirred for 3.5 hours at ambient temperature. The mixture was filtered through a pad of diatomaceous earth that was washed with ethyl acetate (200 mL). The filtrate was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound (5.16 g, 77% yield) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 2.88 (s, 1H), 2.15-2.11 (m, 4H), 1.92-1.85 (m, 4H), 1.75-1.70 (m, 6H); MS (ES−) m/z 162.2 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:30]5[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4ccc(Br)cc4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 416, starting from 2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine and 4-bromophenylboronic acid. Mass spectrum (ESI) 472.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1.[C:18](O)(=[O:21])[CH:19]=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)CCl>[C:13]([C:8]1[C:9]2[O:12][C:19](=[O:20])[CH:18]([OH:21])[C:10]=2[CH:11]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:17])[CH:7]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O

Procedure:
3-(4-hydroxy-3-tert.butylphenyl) propionic acid methyl ester (10.0 g), glyoxylic acid (7.4 g of the 50% solution in water) and p-toluene sulphonic acid (40 mg) are heated in 40 ml ethylene chloride under nitrogen at reflux for 3 hours distilling off all water present and formed during the reaction. The reaction mixtures is washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give 13.0 g of 7-tert.butyl-5-(2-methoxycarbonylethyl)-3-hydroxy-3H-benzofuran-2-one.
Reaction SMILES: [CH3:1][CH:2]([P:6]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])(=[O:10])[O:7][CH2:8][CH3:9])[CH2:3][C:4]#[N:5].N.[H][H]>C(O)C.[Ni]>[NH2:5][CH2:4][CH2:3][CH:2]([P:6]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])(=[O:10])[O:7][CH2:8][CH3:9])[CH3:1]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(OCC)C(C)CC#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(C)CCN

Procedure:
A solution of 17.0 g of ethyl 1-methyl-2-cyanoethyl(diethoxymethyl)phosphinate in 150 ml of ethanol is added to 155.0 g of an 8% solution of ammonia in ethanol. To this are added 10 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure and the crude product is distilled under reduced pressure to give ethyl 3-amino-1-methylpropyl(diethoxymethyl)phosphinate, b.p. 140° C./0.01 mbar, 31P=+47.0 and +46.7 ppm (CDCl3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:27](=[O:29])[CH3:28])[CH:15]2[CH2:16][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.2 mmol) in DCM (22 mL) was added DIEA (0.8 mL, 4.6 mmol) and acetic anhydride (0.42 mL, 4.4 mmol). The mixture was stirred (rt, 16 h). After washing the solution with 1 N NaOH and brine, the organic layer was dried and concentrated to an orange oil (1.15 g, 98%). MS (ESI): mass calcd. for C15H26N2O3, 282.19; m/z found, 283.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C[Al](C)C.[Cl:14][C:15]1[CH:35]=[CH:34][C:18]2[C:19](=[O:33])[C:20]3[C:27]([C:28](OCC)=[O:29])=[N:26][NH:25][C:21]=3[C:22](=[O:24])[NH:23][C:17]=2[CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]2[C:19](=[O:33])[C:20]3[C:27]([C:28](=[O:29])[N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])=[N:26][NH:25][C:21]=3[C:22](=[O:24])[NH:23][C:17]=2[CH:16]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: COCCNCCOC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 0.33 h
Yield: 330.6 %

Procedure:
Bis-(2-methoxyethyl)amine (560 μL, 3.13 mmol) was added to a solution of trimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution was stirred for 20 minutes. A portion (403 μL) of the resulting solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.313 mmol) in toluene (780 μL). The resulting solution was stirred for 24 hours at room temperature and then quenched with an aqueous hydrochloric acid solution (1.8 mL, 1N) and water (15 mL). The aqueous layer was extracted with chloroform (7×25 mL). The organic layers were combined and concentrated on a rotary evaporator. The crude product was purified by flash chromatography eluting with chloroform:2-propanol (99:1-95:5) to give the title compound (421 mg, 67% yield, m.p. 207-209° C.).
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:17]C1C=C(C)C=CC=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH3:17][C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][CH:2]=1)[CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Reactant: Cc1cccc(CBr)c1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1cccc(C)c1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 3-bromomethyltoluene (15 g), a 2M ethanolic solution of sodium ethylate (44.5 cc) and ethyl 2-mercaptoacetate (9.7 g) in ethanol (100 cc). Ethyl (3-methylbenzylthio)acetate (14.4 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]1([C:13]23[CH2:20][CH2:19][C:16]([NH2:21])([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>CN(C=O)C.O>[C:1]1([C:13]23[CH2:20][CH2:19][C:16]([NH:21][S:25]([CH:22]4[CH2:24][CH2:23]4)(=[O:27])=[O:26])([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1
Reactant: NC12CCC(c3n[nH]c4cnc5[nH]ccc5c34)(CC1)CC2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(NC12CCC(c3n[nH]c4cnc5[nH]ccc5c34)(CC1)CC2)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
To a mixture of 4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-amine (0.075 g, 0.267 mmol) in DMF (2.5 mL) was added TEA (0.06 mL, 0.40 mmol) and cyclopropanesulfonyl chloride (0.027 mL, 0.27 mmol, Matrix). The reaction mixture was stirred at ambient temperature for about 16 h. Cyclopropanesulfonyl chloride (0.014 mL, 0.133 mmol, Matrix) was added to the reaction mixture and the reaction continued to stir at ambient temperature for about 4 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.015 g, 15%) as a white solid: LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 386 (M+H)+.