Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:11][CH2:12][N:6]2[CH2:7][CH2:8]3)[CH2:2]1.N1CCC2(CC3CN2CC3)C1.N12CCC(CC1)CC2C(OCC)=[O:33].N12CC(CC1)CC2C(OCC)=O.BrCC1CCOCC1.C([N-]C(C)C)(C)C.[Li+].[N+](C=C)([O-])=O>[Ni]>[NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:8][CH2:7][N:6]2[CH2:12][CH2:11]3)[C:2]1=[O:33]
Reactant: C1CC2(CN1)CC1CCN2CC1
Reactant: CCOC(=O)C1CC2CCN1CC2
Agent: [Ni]
Agent: BrCC1CCOCC1
Agent: C1CC2(CN1)CC1CCN2C1
Product: O=C1NCCC12CC1CCN2CC1

Procedure:
The compounds of Formula 2, wherein u=1, v=2, w=1, x=0, y=2 and z=2, possess the spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine] core and can be prepared in a manner similar to that for the corresponding spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine], as seen in Scheme 11. Ethyl quinuclidine-2-carboxylate can be generated from (4-bromomethyl)tetrahydropyran by the procedures discussed previously for ethyl 1-azabicyclo[2.2.1]heptane-2-carboxylate. The requisite 4-(bromomethyl)tetrahydropyran can be prepared according to procedures found in Burger, et al., J. Am. Chem. Soc. 72:5512 (1950), Thomas, et al., J. Pharm. Pharmacol. 15:167 (1963) and J. Am. Chem. Soc. 115:8401 (1993). Ethyl quinuclidine-2-carboxylate is then deprotonated with lithium diisopropylamide and reacted with nitroethylene. Subsequent treatment with Raney nickel gives directly the spirolactam, spiro[azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-2′-one, by reduction of the nitro group followed by spontaneous cyclization. This lactam is then reduced with lithium aluminum hydride to provide the desired spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine], which is then arylated on the pyrrolidine nitrogen.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Product: Clc1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, light yellow solid (0.28 g, 42%), MS (ISP) m/z=307.3 [(M+H)+], mp 157° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-chloro-phenylboronic acid (0.34 g, 2.17 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH:22]=[CH:23][CH:24]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.O.C1C[O:40][CH2:39]C1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[CH2:25][C:26]4[O:27][C:39](=[O:40])[NH:29][N:28]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(CC(=O)NN)c4)c23)cc1
Reactant: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(Cc5n[nH]c(=O)o5)c4)c23)cc1
Temperature: 25 °C

Procedure:
Heat 0.85 mg (0.183 mmol) of 2-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)acetic hydrazide and 35.5 mg (0.219 mmol) of N,N′-carbonyldiimidazole under reflux in 3 ml of THF for 2 h. After cooling to RT, add to water and extract repeatedly with dichloromethane. Dry the combined organic phases over magnesium sulphate and concentrate under reduced pressure. 79.9 mg (89% of theory) of the target product are obtained as a beige solid.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.17 min; [M+H]+=427.12.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13].[OH-].[Na+].O.Cl>O1CCCC1.CO.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(F)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1-c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Methyl 2-(2,3,4-trifluorophenyl)-5-nitrobenzoate (Reference Compound No. 1-2-(1), 4.37 g, 14.1 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and methanol (30 mL), then 1N aqueous NaOH solution (20 mL) was added thereto, and then the reaction mixture was stirred at room temperature overnight. Water (150 mL) and 1N aqueous HCl solution (30 mL) were added to the reaction mixture to acidify, then ethyl acetate (150 mL) was added thereto, and then separated. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the titled reference compound (4.18 g) as a gray solid. (Yield 100%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Yield: 2.6 %

Procedure:
To a solution of 1-(t-butoxycarbonyl)piperazine (7 g, 1 mol. equiv.) in dichloromethane (ml) at 0° C. under nitrogen was added triethylamine (6.29 ml, 1.2 mol. equiv.). The mixture was vigorously stirred whilst methanesulphonyl chloride (3.49 ml, 1.2 mol. equiv.) was added, dropwise. The mixture was then stirred for twenty four hours. The reaction mixture was washed with a saturated aqueous sodium bicarbonate solution (30 ml) and the organic layer dried using magnesium sulphate. The organic solvent was removed under reduced pressure and the residue purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:2, by volume) to give the title compound (6.93 g). TLC Rf=0.37 (silica, ethyl acetate:hexane, 1:2, by volume). LRMS m/z=282(m+NH4)+. Found: C, 45.25; H, 7.68; N, 10.49. C10H20N2SO4 requires C, 45.43; H, 7.63; N, 10.60%.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH2:26])[N:20]=4)=[CH:14][C:13]=3[F:27])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:34][NH:35][CH2:36][C@H:29]12.C(N(C(C)C)CC)(C)C>C(C(CCCC)CO)C>[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:34][N:35]([C:23]3[CH:24]=[C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([O:11][C:7]5[C:6]6[C:2]([NH2:1])=[N:3][O:4][C:5]=6[CH:10]=[CH:9][CH:8]=5)=[C:13]([F:27])[CH:14]=4)[N:20]=[C:21]([NH2:26])[N:22]=3)[CH2:36][C@H:29]12
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3cccc4onc(N)c34)c(F)c2)n1
Reactant: C1CN[C@H]2CNC[C@H]2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCC(CC)CO
Product: Nc1nc(Nc2ccc(Oc3cccc4onc(N)c34)c(F)c2)cc(N2C[C@H]3CCCN[C@H]3C2)n1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
88 mg (0.23 mmol) of N-{4-[(3-amino-1,2-benzisoxazol-4-yl)oxy]-3-fluorophenyl}-N-(2-amino-6-chloro-4-pyrimidinyl)amine (from example 3) and 114.8 mg (0.91 mmol) of [(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridine together with 294.1 mg (2.28 mmol) of diisopropylethylamine are dissolved in 4 ml of 2-ethylhexanol, and the mixture is stirred at 150° C. for 3 h. After cooling, the reaction mixture is filtered and water is added. The mixture is extracted repeatedly with ethyl acetate, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])=S.CN(C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:6][CH3:5])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:1]
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Reactant: N#CN
Agent: [Pb]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 24 h

Procedure:
Lead cyanamide (3.0 g.) was added to a so;ution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (2.44 g.) in acetonitrile (50 ml.). Dimethylformamide (20 ml.) was added subsequently and the suspension was heated under reflux, with stirring, for 24 hours. Filtration, followed by concentration under reduced pressure and purification of the product by chromatography on a column of silica gel with acetonitrile as eluant and recrystallisation from the same solvent afforded N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 139°- 141°. (Found: C, 47.3; H, 6.6; N, 33.4; S, 12.6. 12.6.C10N16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[Cl:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:25][N:24]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(I)c1
Reactant: OB(O)c1cnc(Cl)nc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cnc(Cl)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 13 using 3-iodo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1) and 2-chloropyrimidin-5-ylboronic acid to afford the title compound as a white powder. UPLC-MS (Condition 1) tR=2.93 min, m/z=394.0 [M+H]+, m/z=392.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.6 Hz, 2H) 7.72 (t, J=7.7 Hz, 1H) 7.90 (d, J=9.0 Hz, 2H) 8.00-8.09 (m, 2H) 8.36 (s, 1H) 9.24 (s, 2H) 10.52 (s, 1H)
Reaction SMILES: [F:1][C:2]1([F:21])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\[C:18](=[O:20])[CH3:19])=[CH:10][C:4]=2[O:3]1.C[O-].[Na+]>CO>[F:21][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH3:16])[S:13]/[C:12]/3=[N:17]\[C:18](=[O:20])[CH3:19])=[CH:10][C:4]=2[O:3]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(C)=O)S1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)/N=c1\sc(C)cn1-c1ccc2c(c1)OC(F)(F)O2

Procedure:
A solution of Example 5 (2.0 g, 6.4 mmol) and sodium methoxide (25% wt/wt, 32.02 mmol) in methanol (25 mL) was heated to 50° C. for two hours. The mixture was concentrated to dryness under reduced pressure, diluted with DCM (300 mL), and washed with water (200 mL) and brine (200 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography using mixture DCM-MeOH (95:5) as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 2.24 (3H), 2.32 (3H), 6.75 (1H), 7.05-7.35 (3H); MS (ESI) 313 (M+H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH3:10].[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>O1CCCC1>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:27]1([OH:30])[CH2:28][CH2:29][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1)([CH3:15])[CH3:14])[CH3:10]
Reactant: CCOC(=O)C(C)C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C1(O)CCN(Cc2ccccc2)CC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Step A To a tetrahydrofuran solution (Aldrich, 1.8 M) of LDA (60 mL, 109 mmol) at −50° C. was added isobutyric acid ethyl ester (Alfa) (12.2 mL, 91 mmol) dropwise. The reaction mixture was stirred −50° C. for 1 h, then a tetrahydrofuran solution (10 mL) of 1-benzyl-piperidin-4-one (12 mL, 68 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 18 h. Aqueous saturated NH4Cl was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl ether. The organic layers were combined, washed with brine, water, dried over MgSO4, and concentrated to give 2-(1-benzyl-4-hydroxy-piperidin-4-yl)-2-methyl-propionic acid ethyl ester as an orange oil (18.5 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][CH:13]([CH3:18])[CH2:14][C:15](=O)[CH3:16]>[Pt].OS(O)(=O)=O.CO>[CH3:16][CH:15]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH2:14][CH:13]([CH3:18])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(=O)CC(C)C
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(C)CC(C)Nc1ccc(F)cc1F
Reaction time: 3 h
Yield: 81.3 %

Procedure:
159.1 g of 2,4-difluoronitrobenzene and 150 g of 4-methylpentan-2-one are mixed in 1.2 1 of methanol with 3 g of concentrated H2SO4 and 5 g of 5% Pt/C, and the mixture is catalytically hydrogenated for 3 hours at 30°-35° under a constant 5 bar of H2. The progress of the hydrogenation is monitored by thin-layer chromatography on silica gel using the mixture petroleum ether/dioxane 4:1 as the mobile phase. When the reaction is complete, the catalyst is filtered off and the solvent is removed by distillation on a rotary evaporator. A brown oil remains which, after removal of some resinous by-product, is rectified in vacuo. The fraction of boiling point 120°-125° at 14 mbar is collected. 173.4 g of N-(1,3-dimethylbutyl)-2,4-difluoroaniline are obtained as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C(N1C=CC(=O)C(O)=C1C)(=O)C.[NH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49].[OH-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:45]([CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(=O)O
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: CC(=O)n1ccc(=O)c(O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O
Yield: 70 %

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), (20 g) and beta-alanine (9 g) are dissolved in 3:2 v/v water/ethanol (500 ml) containing NaOH (10 g) to provide a solution with a pH of at least 13. The solution is refluxed for 15 minutes whereupon it turns from a light orange to an intense red colour. The solution is acidified to pH 7.0 and the ethanol is removed by rotary evaporation. The resulting aqueous solution is washed twice with ethylacetate (100 ml). This solution is then subjected to rotary evaporation until the volume is reduced to 100 ml and this reduced volume of solution is acidified to pH 3.0 to give a white precipitate, which is filtered off to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one in 70% yield, m.p. 156°-157° C. 1-(2'-Carboxyethyl)-3-hydroxy-2-methylpyrid-4-one hydrochloride
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:31][C:28]3[CH:29]=[CH:30][C:25]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[CH:26][CH:27]=3)[N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)C1
Reactant: Oc1ccc(-n2cnnn2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1

Procedure:
A mixture of 3-(4-Chloromethyl-thiazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (From Step 1) (775 mg, 2.56 mmol), 4-tetrazol-1-yl-phenol (415 mg, 2.56 mmol), CsCO3 (1.25 mg, 3.84 mmol) and KI (44 mg, 0.26 mmol) in acetonitrile (20 mL) was heated under reflux overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.63 (2H, d), 7.27(1H, s), 7.17 (2H, d), 5.24 (2H, s), 3.87 (1H, m), 3.79 (1H, m), 3.65 (2H, m), 3.45 (1H, m), 2.40 (1H, m), 2.23 (1H, m), 1.47 (9H, s).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([O:17]O)(C)(C)C.C(OCC)C>[OH-].[Na+].O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:17])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OO
Reactant: O=Cc1ccc2c(c1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc2c(c1)CCCC2
Temperature: 70 °C
Reaction time: 72 h

Procedure:
1,2,3,4-Tetrahydro-6-naphthaldehyde (2.0 g) was suspended in 0.5M aqueous sodium hydroxide solution (125 ml), stirred vigorously and a 70% w/w solution of tertiary butyl hydroperoxide in water (10.3 ml) added. The mixture was heated at about 70° C. for 4 hours and then left to stand at room temperature for 3 days. A frther quantity of a 70% w/w solution of tertiary butyl hydroperoxide in water (10 ml) was added and the mixture heated at about 70° C. for a further 24 hours. The mixture was cooled, diethyl ether (100 ml) added and the phases separated. The aqueous phase was acidified to pH 1 with 2N aqueous hydrochloric acid solution and extracted with diethyl ether (2×100 ml). The organic phases were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 1:1 changing to 1:0, by volume, diethyl ether:pentane to give 1,2,3,4-tetrahydro-6-naphthoic acid (0.62 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>CO.C(Cl)Cl>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c(OC)cc2C1
Yield: 14.1 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (60 mg, 0.26 mmol) and (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (88 mg, 0.26 mmol) were coupled to provide 8-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (20 mg, 14%) as a mustard yellow solid following preparative tlc (10% MeOH-DCM); NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.49 (d, J=8 Hz, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.68 (m, 2H), 7.39 (m, 1H), 7.16 (s, 1H), 6.82 (s, 1H), 3.94 (s, 3H), 3.75 (s, 2H), 3.42 (s, 2H), 3.24 (t, J=7 Hz, 1H), 2.76 (t, J=7 Hz, 2H), 1.33 (d, J=7 Hz, 6H), 1.20 (t, J=7 Hz, 3H); MS (m/e) 546 (M+1); mp 175° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.Cl.[CH3:34][O:35][C:36]([C:38]1([NH2:47])[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37].C(=O)([O-])O.[Na+]>C(Cl)Cl.CC(=O)OCC>[CH3:34][O:35][C:36]([C:38]1([NH:47][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([S:2][CH3:1])=[C:4]([O:12][CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[CH:5]=2)[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: CSc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccc(SC)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
The compound of step 3 (395 mg, 1.31 mmol) was dissolved in DCM (5 ml). DMF (29 mg, 0.39 mmol) and oxalyl chloride (3.9 ml of a 2 M solution in DCM) were added at room temperature. The mixture was stirred for 60 min, evaporated to dryness in vacuo, dissolved in dioxane and evaporated again. The residue was dissolved in DCM (2 ml) and the solution was slowly added with stirring to an ice-cooled mixture of 2-amino-indane-2-carboxylic acid methyl ester hydrochloride (5.42 g, 23.8 mmol), EA and an excess of saturated aqueous sodium hydrogencarbonate solution. After 2 h, the organic layer was separated, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. 582 mg of the title compound were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([C:23](=[O:35])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=3)[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].CO>O>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][C:23]([C@H:14]2[CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]23[CH3:16])[C:20]2[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH2:8][CH2:9]4)=[O:35])=[CH:31][CH:30]=1)([OH:34])=[O:33]
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CCc3ccc(C(=O)O)cc3)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)CCc1ccc(C(=O)O)cc1
Yield: 79 %

Procedure:
A mixture of methyl-17β-[3-(4-carboxyphenyl)propionyl]-estra-1,3,5(10)-triene-3-carboxylate (0.053 g, 0.11 mmoles), K2CO3 (50 mg, 0.36 mmoles), MeOH (9 ml) and H2O (1 ml) was refluxed under argon. Methanol was evaporated and the residue was acidified with dilute HCl. Extracted with EtOAc. The organic layer was washed with H2O, brine, dried and concentrated. The residue was chromatographed (silica gel) eluting with 1% MeOH in CH2Cl2 containing 1% HOAC to give the title compound as a white solid (40 mg, 80%), mp 285°-290° C.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:12][C:13]1[C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[C:17]([C:30]([F:33])([F:32])[F:31])[N:16]=[CH:15][CH:14]=1>>[F:1][CH:2]([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[N:21]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19](=[O:20])[C:18]2[C:17]([C:30]([F:33])([F:31])[F:32])=[N:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=Cc1ccccc1C(F)F
Reactant: Nc1ccnc(C(F)(F)F)c1C(=O)NCCc1ccccc1
Product: O=c1c2c(C(F)(F)F)nccc2nc(-c2ccccc2C(F)F)n1CCc1ccccc1

Procedure:
Prepared analogous to Example 1 starting from 2-(difluoromethyl)benzaldehyde and 4-Amino-N-phenethyl-2-(trifluoromethyl)nicotinamide. 1H NMR (400 MHz, CDCl3) δ 8.88 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.69 (t, 1H), 7.61 (t, 1H), 7.19 (m, 4H), 6.89 (m, 2H), 6.77 (t, 1H), 4.28 (m, 1H), 3.78 (m, 1H), 2.95 (m, 2H). MS m/z 446.4 (M+H)+.