Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH:13]=O>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH:13]=[N:2][OH:3]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cc(Cl)cc(Cl)c1
Reaction time: 2 h

Procedure:
80 ml of ethanol were added to 23.82 g (342.8 mmol) of hydroxylamine hydrochloride. After addition of 28.12 g (342.8 mmol) of sodium acetate, a solution of 50.00 g (285.7 mmol) of 3,5-dichlorobenzaldehyde in 100 ml ethanol was added dropwise within a period of 30 min, the mixture was stirred for 2 h and then allowed to stand overnight. The reaction mixture was concentrated to dryness, 500 ml of CH2Cl2 were then added and the mixture was washed with 400 ml of water. The aqueous phase was washed once with 100 ml of CH2Cl2, the organic phase was dried over Na2SO4, filtered off and concentrated. The residue was used without further purification. Yield: 56.50 g (98%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[CH3:18][C:19]([CH3:35])([CH3:34])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28](O)=[C:29]([CH2:30][CH2:31][CH3:32])[C:24]=2[O:23][N:22]=1>>[CH3:18][C:19]([CH3:34])([CH3:35])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:1][CH2:2][CH2:3][C:4]3[NH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=4)=[C:29]([CH2:30][CH2:31][CH3:32])[C:24]=2[O:23][N:22]=1
Reactant: CCCc1c(O)ccc2c(CC(C)(C)C)noc12
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3[nH]2)ccc2c(CC(C)(C)C)noc12

Procedure:
Using the procedures in Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 3-(2,2-dimethylpropyl)-7-propyl-6-hydroxybenz[4,5]isoxazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]([OH:19])[CH3:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]([OH:19])[CH3:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: C[C@H](O)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: C[C@H](O)CN1CCN(c2ccc(N)cc2)CC1
Yield: 88.1 %

Procedure:
(S)-1-[4-(4-Nitro-phenyl)-piperazin-1-yl]-propan-2-ol (1.60 g, 0.00603 mol) was dissolved in Methanol (35.0 mL) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (90.10, carbon black. Palladium, 0.500 g, 0.0375 mol) under nitrogen. The reaction was then placed on a Parr hydrogenator and was allowed to shake until uptake of hydrogen had ceased (overnight). Catalyst was removed via filtration and filtrate was reduced en vacuo to afford 1.25 g of (5)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol as a white powder. (M+H)=236.21. 1H NMR (400 MHz, DMSO, d6) δ 6.66 (d, 2H, J=8.72 Hz), 6.48 (d, 2H, J=8.72 Hz), 4.53 (s, 2H), 4.26 (d, 1H, J=4.00 Hz), 3.77 (m, 1H), 2.88 (m, 4H), 2.54 (m, 4H), 2.26 (m, 1H), 2.18 (m, 1H), 1.04 (d, 3H, J=6.17 Hz).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][N:13]=[C:12]([S:21][CH3:22])[N:11]=2)[CH2:4]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[C:12]([S:21][CH3:22])[N:11]=2)[CH2:4]1
Reactant: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@H](OC)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CO[C@H]1CCC[C@@H](Nc2nc(SC)ncc2C(=O)O)C1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a stirring solution of ethyl 4-((1R,3S)-3-methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylate (1.4284 g, 4.39 mmol) in ethanol (12.54 mL) was added aqueous sodium hydroxide solution (1 N, 8.78 mL, 8.78 mmol) and the mixture was stirred for 2 h. The reaction was concentrated, diluted with water (50 mL), and then neutralized while stirring with aqueous citric acid solution (2 M, 5.49 mL, 10.97 mmol). The precipitate was filtered, then washed with water (2×50 mL) and dried to afford 4-((1R,3S)-3-methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (1.1679 g, 3.93 mmol, 89% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.22 (s, 1H), 8.65 (d, J=7.03 Hz, 1H), 8.51 (s, 1H), 4.07-4.24 (m, 1H), 3.29-3.33 (m, 1H), 3.26 (s, 3H), 2.46 (s, 3H), 2.15 (d, J=12.10 Hz, 1H), 1.63-1.88. (m, 3H), 1.21-1.48 (m, 4H); MS (ESI) m/z 298.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[NH2:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]1[CH:3]=[C:2]([NH:1][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=2)[CH:15]=[CH:14][C:5]=1[C:6]([CH3:13])=[CH2:12]
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: C=C(C)c1ccc(Nc2ncc(Cl)c(Nc3c(C)cccc3C(=O)NC)n2)cc1CCC(N)=O

Procedure:
A suspension of 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (46 mg), 2-(2,5-dichloropyrimidin-4-ylamino)-N,3-dimethylbenzamide (42 mg), and camphorsulfonic acid (40 μL of a 100 mg/mL aqueous solution) were heated in isopropanol (2 mL) for 4 hours at 120° C. using microwave irradiation. The solvent was evaporated to afford crude 2-(2-(3-(3-amino-3-oxopropyl)-4-(prop-1-en-2-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-N,3-dimethylbenzamide. The crude mixture was dissolved in TFA and allowed to stand for 4 hours, then concentrated. Purification by semi-preparative HPLC provided 2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N,3-dimethylbenzamide as the TFA salt. The non-salt was obtained by stirring the TFA salt in acetonitrile with 300 mg of MP-carbonate (Argonaut, 2.91 mmol/g) for 2 days. The resin was separated by filtration, then washed with methanol and methylene chloride. The filtrate was concentrated and the residue triturated with ethyl ether to provide 14 mg of the neutral compound: 1H NMR (300 MHz, CDCl3 with 5% CD3OD) δ 8.05 (s, 1H), 7.5-7.4 (m, 2H), 7.35 (dd, 1H), 7.3 (d, 1H), 7.15 (d, 1H), 7.1 (dd, 1H), 2.9 (s, 3H), 2.8 (m, 2H), 2.6 (m, 2H), 2.3 (s, 3H) 1.8 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[C:22]2[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[S:27][C:23]=2[N:24]=[CH:25][N:26]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.N>CN(C=O)C>[C:31]([C:28]1[S:27][C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][CH:10]([CH3:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:22]=2[C:29]=1[CH3:30])(=[O:32])[NH2:35]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2-(1-(tert-Butoxycarbonylamino)propan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (250 mg) and TBTU (170 mg) was dissolved in DMF (3 ml) and triethylamine (1900) was added. The mixture was stirred at room temperature for 10 min, then 0.5 ml conc. ammonia was added. The reaction was stirred for 2 h. Then the reaction mixture was concentrated in vacuo and purified by RP-chromatography (water with 0.2% trifluoroacetic acid/methanol 72-100%) to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCCC1>[C:7](#[N:8])[CH:9]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCC=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (165 mL, 0.165 mol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (27 mL, 0.17 mol) in tetrahydrofuran (100 mL). The reaction was warmed to room temperature and then cooled to 0° C. again after stirring for 30 min. To the reaction mixture was added a solution of hexanal (18 mL, 0.15 mol) in tetrahydrofuran (150 mL). The reaction was stirred overnight, allowed to warm up to room temperature. The reaction was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0 to 15% EtOAc in hexanes) to provide the desired product (˜17 g, 92%) as a mixture of cis and trans isomers. MS calculated for C8H14N(M+H)+: m/z=124.113. Found: 124.3.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:18][CH2:17]N=[CH:15]1)=[O:13])[CH2:8]2.[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([O:28]CCNC)=[CH:24][CH:23]=1.O>C(Cl)Cl>[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:17][CH2:18][N:14]([CH3:15])[C:12]([NH:11][CH:2]2[CH:1]3[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]2[CH2:9]4)[CH2:10]3)=[O:13])=[CH:24][CH:23]=1
Reactant: CNCCOc1ccc(C(=O)OC)cc1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1C=NCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(OCCN(C)C(=O)NC2C3CC4CC(C3)CC2C4)cc1

Procedure:
A solution of 4H-Imidazole-1-carboxylic acid adamantan-2-ylamide 0.5 g (2.04 mmol) and 4-(2-Methylamino-ethoxy)-benzoic acid methyl ester 426.8 mg (2.04 mmol) in methylene chloride 10 ml was stirred at room temperature for 2 days. Water was added, the organic phase extracted, dried and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluant DCM/MeOH: 100/0 to 95/05) yielding 596 mg as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][C@H:17]3[C@@H:21]([OH:22])[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:36][C:30]([C:32]([F:35])([F:34])[F:33])=[O:31].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][C@H:17]3[C@@H:21]([OH:22])[CH2:20][NH:19][CH2:18]3)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CNC[C@@H]1O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of cis-tert-butyl 3-(2-(3-fluorophenyl)pyrimidine-5-carboxamido)-4-hydroxypyrrolidine-1-carboxylate (1.22 g, 3.03 mmol) in DCM (6 mL) was added TFA (2 mL). The solution stirred at room temperature for 3 hrs and then diluted with toluene (5 mL) and the solvent removed to give a solid, cis-2-(3-fluorophenyl)-N-(4-hydroxypyrrolidin-3-yl)pyrimidine-5-carboxamide-TFA salt (1.26 g, 98%). LC/MS (M+H)=303.1 observed, 303.13 expected.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1(Cl)[CH:6]([CH3:7])[C:5]1([C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)C.[CH3:23]O>>[CH3:4][C:5]([C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH3:23])=[O:16])=[CH:11][CH:10]=1)=[CH:6][CH3:7]
Reactant: CO
Reactant: CC1C(Cl)(Cl)C1(C)c1ccc(OC(C)(C)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC=C(C)c1ccc(OC(C)(C)C(=O)OC)cc1

Procedure:
Sodium hydride (15.1 g., 0.36 mole, 57% in oil dispersion) was placed in a 2-liter flask and rinsed three times with pentane to remove the oil. Anhydrous dimethylsulfoxide (240 ml.) was then added, and the flask was evacuated and flushed with nitrogen. The mixture was heated to 75°-80°C. for 45 minutes, then cooled in an ice bath. A solution of 133.2 g. of ethyltriphenylphosphonium bromide in 720 ml. of dimethylsulfoxide was then added, the mixture stirred for 15 minutes and then treated with a solution of 70.8 g. (0.30 mole) of methyl 2-(p-acetylphenoxy)-2-methylpropionate in 120 ml. of dimethylsulfoxide. The reaction mixture was stirred for three hours at room temperature and then poured into water. The organic layer was separated, washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate to give 81.8 g. of methyl 2-[p-(1,2-dimethylvinyl)phenoxy]-2-methylpropionate as an oil (mixture of geometric isomers). c. 2-[p-(2,2-Dichloro-1,3-dimethylcyclopropyl)phenoxy]-2-methylpropionic acid [I; A, A', R1 and R3 are CH3, R, R3' and Q are H, R 2 and R2' are Cl, and n is 0; para orientation] was prepared from 24.8 g. of methyl 2-[p-(1,2-dimethylvinyl)phenoxy]-2-methylpropionate, 28 g. of potassium t-butoxide and 50 ml. of chloroform in 500 ml. of pentane according to the procedure described above in Example 1, part (b). The methyl ester thus obtained was hydrolyzed in the usual manner with sodium hydroxide in 95% methanol. The acid fraction thus obtained was recrystallized from a benzene-hexane mixture to give 12.5 g. of 2-[p-(2,2-dichloro-1,3-dimethylcyclopropyl)phenoxy]-2-methylpropionic acid, m.p. 138°-145°C. (mixture of geometric isomers).
Reaction SMILES: [C:1]1([C:7]2C=C[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C=CC=CC(O)=O)C=CC=CC=1.C1(CCC(O)=O)C=CC=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: O=C(O)C=CC=Cc1ccccc1
Agent: O=C(O)CCc1ccccc1
Product: O=C(O)CCCCc1ccccc1

Procedure:
The same procedure as in Example 31 was repeated except that 4-phenylbenzoic acid, 5-phenyl-2,4-pentadienoic acid and 3-phenylpropionic acid were used, respectively, in place of 5-phenylvaleric acid to obtain N-cyclopropylmethyl-7α-(4-phenylbenzoylamino)-6,14-endoethenotetrahydronorthebaine 41 (88%), N-cyclopropylmethyl-7α-(5-phenyl-2,4-bentadienoylamino)-6,14-endoethenotetrahydronorthebaine 42 (94%) and N-cyclopropylmethyl-7α-(3-phenylpropionylamino)-6,14-endoethenotetrahydronorthebaine 43 (84%), respectively.
Reaction SMILES: [N+:1]([CH2:4][C:5]([S-:7])=S)([O-:3])=[O:2].[K+].[K+].[N+]([CH2:13]C([S-])=S)([O-])=O.[CH:17]([NH2:23])([C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:18].S(OC)(OC)(=O)=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH3:18][CH:17]([NH:23][C:5]([S:7][CH3:13])=[CH:4][N+:1]([O-:3])=[O:2])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(N)C(C)(C)C
Reactant: O=[N+]([O-])CC(=S)[S-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CSC(=C[N+](=O)[O-])NC(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To an aqueous solution of dipotassium nitrodithioacetate (300 g 15% by weight) was added pinacolylamine (32 g) over 1 hour. After heating to 60° C. and maintaining this temperature for 4 hours, the reaction mixture was cooled to ambient temperatures and stirred overnight. Benzyltrimethylammonium chloride (3 g ), was then charged, followed by dimethyl sulphate (66 g) over one hour. After stirring overnight, the reaction mixture was extracted three times with 50ml aliquots of dichloromethane. After drying over MgSO4, the combined organic phases were concentrated and the residue recrystallised from 2-propanol to give 13 g (33%) of the title compound (m.p. 69° C.) which is believed to be novel.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[CH:44]=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cncc(-c2cc(C)c(Br)c(C)c2)c1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cncc(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-bromo-3,5-dimethyl-phenyl)-5-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][N:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:14]2=[O:17])[CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[F:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[CH2:12][CH:11]3[CH:15]([CH2:16][NH:9][CH2:10]3)[C:14]2=[O:17])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1C2CNCC2CN1c1ccc(OC(F)(F)F)cc1
Yield: 96 %

Procedure:
To a solution of saturated hydrochloride in ethyl acetate (40 mL) was added 4-Oxo-5-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (3.0 g, 7.8 mmol) with stirring. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure to yield the title compound (2.4 g, 96%). 1H NMR (300 MHz, d6-DMSO): δ 9.11 (bs, 1H), 7.81-7.76 (m, 2H), 7.40-7.38 (m, 2H), 4.10-4.08 (m, 1H), 3.73-3.70 (m, 1H), 3.55-3.15 (m, 6H); LC-MS: [M+1]+ 287.8.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:39])[C:20]([C:36]([OH:38])=[O:37])=[CH:21][N:22]3CC3C=CC(OC)=CC=3OC)=[CH:17][C:16]=2[F:40])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.ClCCl.Cl>FC(F)(F)C(O)=O.C(OCC)C>[CH2:1]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:39])[C:20]([C:36]([OH:38])=[O:37])=[CH:21][NH:22]3)=[CH:17][C:16]=2[F:40])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C(NCc5ccccc5)C4)nc32)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)c1c[nH]c2nc(N3CC(O)C(NCc4ccccc4)C3)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 244B (0.027 g) in trifluoroacetic acid (2 mL) was heated at 75° C. for 18 hours, and concentrated with a toluene azeotrope; and the residue was purified on a reverse phase HPLC on a C8 column with 10-95% acetonitrile in water containing 0.1% trifluoroacetic acid to provide an oily compound. A solution of the oily compound in 1:1 of methanol/dichloromethane was treated with 2N HCl in diethyl ether (0.5 mL), and concentrated. NMR (DMSO-d6) δ ppm 13.34 (m, 1H), 9.72 (bs, 2H), 8.51 (d, 1H), 8.05 (d, 1H), 7.63 (m, 2H), 7.44 (m, 3H), 4.74 (bs, 1H), 4.40-4.00 (m, 5H), 3.70 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=O.S(=O)(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].N>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1
Reactant: NNC(N)=S
Reactant: O=C(O)CCCCCBr
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1nnc(CCCCCBr)s1
Yield: 59 %

Procedure:
6-Bromohexanoic acid (5.35 g, 27.4 mmol), concentrated sulphuric acid (15 mL), and thiosemicarbazide (3.0 g, 32.9 mmol) were slowly heated to 80-90° C. for 12 h. After cooling, the content was poured onto crushed ice. The mixture was neutralized with 10% aqueous ammonia and extracted with ethyl acetate (3×100 mL). The organic extracts were washed with 10% Na2CO3 (2×50 mL), water (100 mL), and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel 60 (70-230 mesh) eluted with CH2Cl2:MeOH 19:1 to give the product as a solid, mp 128-130° C., in 59% yield (4.03 g, 16.2 mmol). 1H NMR (300 MHz, CDCl3) δ 1.51-1.60 (m, 2), 1.71-1.79 (m, 2), 1.81-1.92 (m, 2), 2.92 (t, 2, J=7.5 Hz), 3.40 (t, 2, J=6.9 Hz), 5.33 (s, 2); 13C NMR (75 MHz, CDCl3) δ 26.9, 28.1, 29.3, 31.8, 35.0, 158.1, 168.2; HRMS (ESI+, m/z) calculated for C7H13BrN3S 250.0014. observed 250.0005 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[O:16][CH:15]=[N:14][C:13]=1[C:17]([O:19]CC)=[O:18].[OH-].[K+].S(=O)(=O)(O)O>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[O:16][CH:15]=[N:14][C:13]=1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1ncoc1-c1ccc([N+](=O)[O-])cc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-c1ocnc1C(=O)O
Temperature: 25 °C

Procedure:
To 780 ml of water were added 15.6 g (0.053 mol) of the 5-(2-methoxy-4-nitrophenyl)-4-carboethoxyoxazole prepared in (1) above and 24.0 g (0.107 mol) of a 25% aqueous solution of potassium hydroxide, and the mixture was allowed to react at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 2 with 30% sulfuric acid. The crystals thus precipitated were collected by filtration to obtain the title compound as a wet cake weighing 41.3 g and having a water content of 68%. That is, the yield of the compound was 13.2 g (0.05 mol, 93.9% based on the 5-(2-methoxy-4-nitrophenyl)-4-carboethoxyoxazole).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2([CH3:23])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[C-:24]#[N:25].[K+]>C1(C)C=CC=CC=1>[CH3:23][C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:24]#[N:25])[CH:13]2[CH:9]1[CH2:10][N:11]([CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12]2
Reactant: CC1(c2cccc(I)c2)C2CN(CCCc3ccccc3)CC21
Reactant: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(c2cccc(C#N)c2)C2CN(CCCc3ccccc3)CC21
Temperature: 80 °C
Yield: 44.2 %

Procedure:
To a degassed solution of 6-(3-iodophenyl)-6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hexane (Example 86, 490 mg, 1.18 mmol) in toluene (20 ml) was added tetrakistriphenylphosphine palladium (0) (0.68 g, 0.60 mmol) and a finely crushed mixture of potassium cyanide (320 mg, 5.0 mmol) and neutral activated alumina (640 mg) under nitrogen. The reaction mixture was heated to 80° C. for 3 h, and then at reflux for 30 minutes before cooling to room temperature and concentrating in vacuo. The mixture was absorbed onto silica gel (7 g) and then purified by chromatography on silica gel (100 g) eluting with hexane:ethyl acetate (95:5 and then 50:50) to give a red solid (165 mg, 44%).