Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].Cl>CCOCC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[C:27]([N:6]2[CH2:5][CH2:4][N:3]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:8][CH2:7]2)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: c1nc(N2CCNCC2)c2cc[nH]c2n1
Reactant: O=C(O)C(Cc1c[nH]cn1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Product: O=C(C(Cc1c[nH]cn1)c1ccc(Cl)c(Cl)c1)N1CCN(c2ncnc3[nH]ccc23)CC1

Procedure:
2-(3,4-Dichlorophenyl)-3-(1H-imidazol-4-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one was prepared by substituting 5-piperazin-1-yl-1H-indazole with 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride and substituting (D)-Boc-4-chlorophenylalanine with 2-(3,4-Dichlorophenyl)-3-(1H-imidazol-4-yl)-propionic acid in Example B-1, Step 2. The free amine was converted to HCl salt by treatment with HCl in Ether. 1H NMR (CD3OD, 400 MHz) δ 8.76 (s, 1H), 8.32 (s, 1H), 7.52 (m, 2H), 7.38 (s, 1H), 7.29 (m, 2H), 6.92 (s, 1H), 4.58 (m, 1H), 3.70-4.20 (m, 7H), 3.63 (m, 1H), 3.43 (m, 1H), 3.16 (m, 1H). LCMS (APCI+) m/z 470, 472, 474 [M+H]+; Rt=2.15 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:19]1([C:25]2[CH2:29][C:28](=[O:30])[NH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:28]1[CH:29]=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:26][N:27]=1
Reactant: O=C1CC(c2ccccc2)=NN1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Oc3cc(-c4ccccc4)[nH]n3)c2cc1OC

Procedure:
Using an analogous procedure to that described for Example 1, 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (134 mg, 0.5 mmol) was reacted with 3-phenyl-4,5-dihydro-1H-pyrazol-5-one (160 mg, 1 mmol), (J. Org. Chem., 1967, 32, 3321-3324), in the presence of sodium hydride (40 mg, 1 mmol, prewashed with THF) in DMF (3 ml) to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline as the free base. The free base was dissolved in a mixture of methylene chloride/methanol (1/1) and 3M hydrochloric acid in methanol was added. The volatiles were removed by evaporation to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline hydrochloride (155 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[N:5]=[CH:4][N:3]=1.[S:10](Cl)(Cl)=O>C(Cl)(Cl)Cl.CO>[NH2:9][C:6]1[C:7]2[C:2](=[N:1][S:10][N:8]=2)[N:3]=[CH:4][N:5]=1
Reactant: Nc1ncnc(N)c1N
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1ncnc2nsnc12

Procedure:
A flask was charged with 19.78 g. (0.15 mole) of 4,5,6-triaminopyrimidine and 163.0 g. (137 mole) of thionyl chloride and the mixture stirred at reflux for 18 hours. The dark orange reaction mixture was evaporated to dryness on the rotary evaporator and to the residue was added 500 ml. water and 40 ml. methanol. The resulting solution was adjusted to a pH of 7.5-8.0 with saturated sodium bicarbonate solution and heated to reflux. The hot mixture was filtered and the filtrate cooled to 0°-5° C. in an ice-bath. The solid was collected by filtration, washed twice with 50 ml. ice water and twice with 50 ml. ether. The resulting tan product was dried in vacuo at 70° C. overnight to afford 18.2 g. (79%) of product. M.p. 247°-249° C.; tlc on silica gel in chloroform-methanol (8:1) showed one spot at Rf =0.4.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[N:11]1([CH2:17][CH2:18][NH:19][C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
A 50 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.187 mL, 1.77 mmol), 2-Morpholin-4-yl-ethylamine (0.299 g, 2.30 mmol) and dioxane (9.0 mL). To the solution, diisopropyl ethyl amine (0.463 mL, 2.66 mmol) was added dropwise and allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜30 mL), and with brine (2×˜30 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording (2-Morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine as a yellow solid (0.315 g, 1.26 mmol, 71% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=1>CO.C(Cl)Cl>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:13][C:10]2[CH:11]=[CH:12][C:3]3[N:2]([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:9]=2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCCCc2cc(N)ccc21
Solvent: CO
Solvent: ClCCl
Product: CN1CCCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4NS(C)(=O)=O)n3)ccc21

Procedure:
Following the procedure of Example 101b, 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (48 mgs, 0.27 mmol) and N-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide (0.9 eq) were reacted except that the ISCO chromatography gradient was 0% to 10% MeOH/CH2Cl2 and the final product was triturated from 4 mL of EtOAc with hexane to give N-{2-[5-Chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide (30.6 mgs) as an off-white/grey solid. MP=170-172° C. 1H-NMR (CDCl3) δ δ 7.88 (s, 1H), 7.50-7.48 (m, 1H), 7.36-7.33 (m, 1H), 7.23 (s, 1H), 7.17-7.13 (m, 2H), 6.95-6.89 (m, 3H), 6.68 (s, 1H), 6.63 (br s, 1H), 2.71-2.68 (m, 8H), 2.50-2.47 (m, 2H), 1.63-1.55 (m, 2H), 1.42-1.38 (m, 2H); LC/MS (ESI+): 273 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][CH:20]([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>O1CCOCC1.C(OCC)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH:20]([F:19])[F:29])=[CH:23][CH:24]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine prepared as described in Example 1.B. (1.09 g, 4.21 mmol) and 4-(difluoromethoxy)benzenamine (1.34 g, 8.42 mmol) in 1,4-dioxane (15 mL) was heated in a sealed tube at 100° C. for 16 h. The dark slurry was cooled to r.t. and diluted with diethyl ether. The solid was collected by flitration and triturated with ethyl acetate: hexane (1:9) and dried to give a tan solid (1.3 g, 81%) which was used directly.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[C:12]([N+:22]([O-:24])=[O:23])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][C@H:9]3[CH3:25].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[CH3:25][C@@H:9]1[CH2:10][C:11]2[C@:16]([CH3:17])([CH2:15][CH2:14][C:13](=[O:21])[C:12]=2[N+:22]([O-:24])=[O:23])[C@@H:18]2[C@@H:8]1[C@H:5]1[C@@:3]([CH2:20][CH2:19]2)([CH3:4])[C:2](=[O:1])[CH2:7][CH2:6]1
Reactant: C[C@@H]1CC2=C([N+](=O)[O-])C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CO
Product: C[C@@H]1CC2=C([N+](=O)[O-])C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
A solution of 17β-hydroxy-7α-methyl-4-nitroandrost-4-en-3-one (4.2 g, 12.1 mM) in acetone (400 ml) is cooled to 0° C. and is treated with Jones reagent (4.0 ml). Any excess reagent is decomposed by addition of methanol. The solids are filtered off and the filtrate is concentrated to a green solid. This material is purified by flash chromatography on silica gel to give 7α-methyl-4-nitroandrost-4-ene-3,17-dione (aqueous acetone).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:12]([CH3:19])=[C:11]2[C:20]#[N:21])[CH:6]=[CH:7][C:8]=1F)#[N:2].O.[NH2:23][NH2:24]>C(O)CCC>[NH2:2][C:1]1[C:3]2[C:8](=[CH:7][CH:6]=[C:5]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:12]([CH3:19])=[C:11]3[C:20]#[N:21])[CH:4]=2)[NH:24][N:23]=1
Reactant: CC1=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C(C)N1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CC1=C(C#N)C(c2ccc3[nH]nc(N)c3c2)C(C#N)=C(C)N1
Yield: 56.5 %

Procedure:
A mixture of 4-(3-cyano-4-fluorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (9.5 g, 34.14 mmol), from Synthetic Example 1, and hydrazine hydrate (10 g, 312 mmol) in n-butyl alcohol (75 mL) was kept at 80° C. for 5 hr. The mixture was cooled and concentrated. Sodium bicarbonate solution (sat.) was added to the residue, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to afford 4-(3-amino-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (5.6 g, 57.01%) as a pale yellow solid (Cpd. No. 82, Table 2). 1H-NMR (300 MHZ, DMSO-D6): δ=11.39 (br. s, 1H), 9.47 (br. s, 1H), 7.50 (m, 1H), 7.20 (d, 1H), 7.11 (dd, 1H), 5.34 (br. s, 2H), 4.34 (s, 1H), 2.01 (s, 6H) ppm.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][O:22]CC2C=CC=CC=2)[CH:16]=[CH:15][C:14]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>C(O)C.[C].[Pd]>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][OH:22])[CH:16]=[CH:15][C:14]=1[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH3:38])=[CH:35][CH:36]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(OCCOCc3ccccc3)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Cc2ccc(OCCO)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 5-[2-(benzyloxy)ethyloxy]-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.022 g) in ethanol (1 mL) was added 10% palladium-carbon powder (0.0082 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give 2-(4-ethylbenzyl)-5-(2-hydroxyethyloxy)phenyl β-D-glucopyranoside (0.013 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:6][CH:7]=1
Reactant: Clc1ccc(CCNCc2ccncc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N(CCc1ccc(Cl)cc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 7.4 g. portion of 4-[2-(4-chlorophenyl)ethylaminomethyl]pyridine was dissolved in 50 ml. of dichloromethane, and to it were added 4 g. of potassium carbonate and 4 g. of methanesulfonyl chloride. The mixture was stirred at ambient temperature overnight, and then 100 ml. of additional dichloromethane was added, followed by 200 ml. of water. The organic phase was separated, washed with water, dried and concentrated under vacuum. The residue was chromatographed on silica gel, using acetone as the eluant. The product-containing fractions were combined and evaporated, and the residue crystallized upon standing. The solids were triturated with petroleum ether and filtered and dried to obtain 4.0 g. of the desired product, m.p. 96°-99°.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][CH2:7][CH2:8][C@@:9]32[C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]3)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([CH:35]=2)[C:33]#[N:34])O1>>[NH2:17][C:11]1[O:12][CH2:13][C:14]([F:16])([F:15])[C@@:9]2([C:18]3[C:5](=[CH:4][CH:3]=[C:2]([C:28]4[CH:29]=[N:30][CH:31]=[C:32]([CH:35]=4)[C:33]#[N:34])[CH:19]=3)[CH2:6][CH2:7][CH2:8]2)[N:10]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: NC1=N[C@@]2(CCCc3ccc(Br)cc32)C(F)(F)CO1
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CCC3)N=C(N)OCC2(F)F)c1
Yield: 72 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-7-bromo-5′,5′-difluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.1) with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile yielded the title compound (72% yield) as an off-white solid. MS (ISP): m/z=355.2 [M+H]+.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=O.[CH3:31][C:32]1[C:36]([NH2:37])=[C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:34][N:33]=1>CN(C)C=O.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:37][C:36]1[C:32]([CH3:31])=[N:33][NH:34][C:35]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
311 mg of hydroxybenzotriazole and 445 μl of diisopropylcarbodiimide were added to a solution of 160 mg of 3-methoxybenzoic acid in 10 ml of dimethylformamide, after which 200 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine were added; the mixture was then stirred at RT for 12 h, after which water was added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 4 C17H15N3O2 (293.33); MS (ESI) 294 (M+H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:24]=[CH:23][C:19]([CH2:20][OH:21])=[C:18]([F:25])[CH:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(=O)O)c(F)c3)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(CO)c(F)c3)CC2)CC1
Temperature: 0 °C

Procedure:
7.8 g of 4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-2-fluorobenzoic acid are added to a suspension of 4.5 g of lithium aluminium hydride in 150 ml of dry ether and the mixture is stirred under reflux for 23 hrs. The suspension is cooled to 0° C., treated cautiously with 40 ml of water and then with 150 ml of 3N sulfuric acid, extracted with ether and the organic phase is dried over sodium sulfate, filtered and the filtrate is evaporated. Chromatography of the residue on silica gel with methylene chloride/acetone (95:5) gives 4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-2-fluorobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].[H][H]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCN(CC)CCc1ccc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: C1CCOC1
Product: CCN(CC)CCc1ccc(N)cc1Cl
Reaction time: 2.5 h

Procedure:
A suspension of 2.00 g (7.790 mmol) [2-(2-chloro-4-nitro-phenyl)-ethyl]-diethyl-amine and 0.80 g Raney nickel in THF was hydrogenated for 2.5 h at RT and 25 psi hydrogen pressure. The catalyst was filtered off and the filtrate evaporated down i. vac.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.CN(C=O)C.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CCOC(C)=O>[N:22]1([C:2]2[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 0.397 mmol) in pyrrolidine (1.0 ml) was added DMF (1.0 ml). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the 3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (100 mg, 91%).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH:20]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:23]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.O1CCCC1>[Pt]=O.CO>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:23]=3)[CH2:20][CH2:21]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CC=C(c3cn(-c4ccccc4)c4ccccc34)CC1)O2
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(c3cn(-c4ccccc4)c4ccccc34)CC1)O2
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2,3-Dihydro-2,4,6,7-tetramethyl-2-[[1,2,3,6-tetrahydro-4-(1-phenyl-3-indolyl)-1-pyridyl]methyl]-5-benzofuranamine (0.36 g), platinum oxide (72 mg), tetrahydrofuran (2 mL) and methanol (4 mL) was stirred for 3.5 hours at 60° C. under hydrogen atmosphere. The mixture was cooled, the catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=5:1) to afford 2,3-Dihydro-2,4,6,7-tetramethyl-2-[[4-(1-phenyl-3-indolyl)-1-piperidinyl]methyl]-5-benzofuranamine. This was dissolved in methanol and to the resulting solution 1 equivalent of oxalic acid solution in methanol was added. The mixture was concentrated and to the residue was added ethanol and diethyl ether. The resulting powdery product was collected to afford the 0.10 g of the title compound. Yield 24%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:46][CH2:47][OH:48]>CC(=O)CC>[OH:48][CH2:47][CH2:46][N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:12]=[C:11]([CH3:13])[O:10][N:9]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)no1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(CCO)CC4)CO6)cc3)c(C)c2)no1
Reaction time: 30 h
Yield: 37.6 %

Procedure:
A stirred solution of 5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E3 in WO 96/19477, 0.44 g, 0.87 mmole) in 2-butanone (30 ml) was treated with potassium carbonate (0.36 g, 2.6 mmole) and 2-chloroethanol (0.18 ml, 2.6 mmole) and heated under reflux for 56 hours, then additional potassium carbonate (0.36 g, 2.6 mmole) and 2-chloroethanol (0.18 ml, 2.6 mmole) added. Reflux was continued for a further 30 hours, then the mixture was concentrated in vacuo and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried, concentrated in vacuo and the residue chromatographed on silica gel eluting with 0-10% methanol/chloroforn to afford the title compound as a pale yellow oil (0.18 g, 38%). This was converted to its hydrochloride salt and crystallised from acetone mp. >230° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@@H:26]([O:27][CH:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29]OS(C3C=CC(C)=CC=3)(=O)=O)[NH:25][C:24]2=[O:47])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:48].[Li+].CN(P(N(C)C)(N(C)C)=O)C>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@@H:26]([O:27][CH:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29][Br:48])[NH:25][C:24]2=[O:47])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCC(O[C@H]2NC(=O)[C@H]2NC(=O)[C@H](Cc2ccccc2)NC(=O)CCc2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@@H]1OC(CBr)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
A mixture of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-{2-(p-toluenesulfonyl)oxy-1 -phenylethoxy}azetidin-2-one (160 mg, 0.244 mmol), lithium bromide (133 mg, 1.525 mmol) and HMPA (4 ml) was stirred at 60° C. for 1.5 hrs. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:2) as eluent and 100 mg (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-(2-bromo-1-phenylethoxy)-azetidin-2-one as white foam was obtained in 72% yield.