Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:11])[CH3:21]
Reactant: CNCCc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)CCc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of [2-(4-chloro-2-nitro-phenyl)-ethyl]-methyl-amine (29.8 g, 0.14 mole) and ethyl bromoacetate (23.2 g, 0.14 mole) in acetonitrile (500 mL) containing potassium carbonate (9.6 g, 0.07 mole) was stirred at room temperature overnight. The mixture was evaporated in vacuo, water was added to the residue and then extracted with dichloromethane (2×200 mL). The combined organic layers were washed with saturated sodium chloride (300 mL), dried and concentrated. Purification by flash column chromatography (silica gel, methylene chloride) provided 22.5 g of the title compound as a brown oil. 1H NMR (DMSO): 7.98 δ (d, 1H); 7.68 δ (dd, 1H); 7.52 δ (d, 1H); 4.00 δ (m, 2H); 3.20 δ (s, 2H); 2.88 δ (t, 2H); 2.68 δ (t, 2H); 2.25 δ (s, 3H); 1.10 δ (t, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4](=[O:23])[CH:5]([CH2:20][C:21]#[CH:22])[C:6]([NH:8][S:9](/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:11])=[O:10])=[O:7])[CH3:2]>C(NC1C=CC=CC=1)C>[CH2:24]([N:3]([C:1]1[CH:21]=[CH:20][CH:5]=[CH:4][CH:2]=1)[C:4](=[O:23])[CH:5]([CH2:20][C:21]#[CH:22])[C:6]([NH:8][S:9](/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:10])=[O:11])=[O:7])[CH3:25]
Reactant: C#CCC(C(=O)NS(=O)(=O)/C=C/c1ccccc1)C(=O)N(CC)CC
Solvent: CCNc1ccccc1
Product: C#CCC(C(=O)NS(=O)(=O)/C=C/c1ccccc1)C(=O)N(CC)c1ccccc1
Yield: 16.1 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (1.04 g) obtained in Example 215 (2) and N-ethylaniline (430 μL). This was purified by silica gel column chromatography to give the title compound (95 mg) as a white powder.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].CN(C)C=O.Br[CH2:20][CH2:21][C:22]([CH3:30])([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CO.O>[CH3:30][C:22]([CH3:29])([CH2:21][CH2:20][NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)(C)CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)(C)CCNS(=O)(=O)c1ccccc1
Temperature: 70 °C

Procedure:
Benzenesulphonamide (9.6 g, 61.1 mmol) was added to a stirred solution of sodium methoxide (1.6 g, 29.6 mmol) in methanol (100 ml). The clear solution was evaporated to dryness, then dimethyl formamide (100 ml) and ethyl 5-bromo-3,3-dimethyl-pentanoate (7.0 g, 32.8 mmol) were added and the mixture was heated for eight hours at 70° C. The solution was then poured into water (600 ml), the mixture was extracted with ether and the ether phase, after being dried over sodium sulphate, was evaporated. Treatment of the solid residue with a mixture of toluene and cyclohexane (9:1) left most of the unreacted benzenesulphonamide undissolved. After filtration, the solution was evaporated and the residue was purified by chromatography on silica gel with a mixture of methylene chloride and ethanol (98:2). Yield: 4.6 g (50% of theory), oily substance, nD20 =1.5083.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)=O)cc1-n1nc2ccccc2n1

Procedure:
The crude reaction product 2(2-hydroxy-5-acetylphenyl)2H-benzotriazole (2H5A) is then o-acetylated with an acetic anhydride/pyridine mixture, and after reflux, 2(2-acetoxy-5-acetylphenyl)2H-benzotriazole (2A5A) was produced. The 2(2-acetoxy-5-acetylphenyl)2H-benzotriazole (2A5A) is a key intermediate in the process, and in purified form served as the starting material for the two carbinols.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][N:6]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:4].O.[OH-].[Li+:22]>>[CH2:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([N:6]2[CH2:7][CH2:8][CH:5]2[C:3]([O-:4])=[O:2])[CH2:14][CH2:13]1)=[O:16])[CH3:19].[Li+:22]
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1

Procedure:
The reaction of ethyl 4-(2-(methoxycarbonyl)azetidin-1-yl)piperidine-1-carboxylate 19K and lithium hydroxide monohydrate yielded lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate as light yellow solid (quant.). MS ISP (m/e): 257.1 (100) [(M+H)]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl[CH2:35][CH2:36][CH2:37][S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39]>>[CH3:42][N:41]([CH3:43])[S:38]([CH2:37][CH2:36][CH2:35][O:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)(=[O:40])=[O:39]
Reactant: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Reactant: CN(C)S(=O)(=O)CCCCl
Product: CN(C)S(=O)(=O)CCCOc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-[7-hydroxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Intermediate H) and 3-chloro-N,N-dimethylpropane-1-sulfonamide (Intermediate F). High vacuum drying gave the title compound (15 mg, 15%): HPLC MS RT=0.24 min, MH+=600.4; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 1.07 (6H, t), 2.18-2.27 (4H, m), 3.04-3.13 (2H, m), 3.27-3.36 (4H, q), 3.51 (2H, d), 3.66 (2H, t), 3.98-4.02 (2H, m), 4.21-4.36 (6H, m), 4.56-4.59 (2H, m), 7.49 (1H, d), 8.02 (1H, dd), 8.08 (1H, d), 8.96 (1H, d), 9.04 (1H, dd), 9.50 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16](Cl)=[C:15]([C:18]#[N:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[C-:25]#[N:26].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16]([C:25]#[N:26])=[C:15]([C:18]#[N:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: [C-]#N
Reactant: C#CCOc1cc(-n2c(Cl)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2c(C#N)c(C#N)n(CCC)c2=O)c(F)cc1Cl

Procedure:
The product of Example 4, 1-(4-chlorophenyl)-5-chloro-4-cyano-3-phenyl-1,3-dihydro-2H-imidazol-2-one (V) (0.94 g, 2.8 mmol) was stirred in 25 mL dimethylformamide. To this mixture was added KCN (0.6 g, 8.5 mmol) and the resulting mixture was heated to reflux for ten minutes. The mixture was then allowed to cool, poured onto water, extracted with ethyl acetate, dried, filtered, and evaporated via standard techniques. Recrystallization with ethyl acetate/heptane gave 0.5 g of 1-(4-chlorophenyl)-4,5-dicyano-3-phenyl-1,3-dihydro-2H-imidazol-2-one (VI) as an orange solid (m.p. 182°-4° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:16]=[C:17]([F:19])[CH:18]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(Br)c3)n2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4cccnc4)c3)n2)nc1
Yield: 47.7 %

Procedure:
In a similar fashion, 3-(5-fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (60 mg, 0.154 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (50.4 mg, 0.309 mmol), and Pd(PPh3)4 (17.8 mg, 0.015 mmol), in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a selaed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 50% to 70% ethyl acetate in hexane afforded 24.7 mg (48%) of 3-(5-fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 8.92 (d, 1H), 8.71 (m, 2H), 8.31 (s, 1H), 8.30 (dd, 1H), 8.00 (m, 2H), 7.62 (td, 1H), 7.57 (td, 1H), 7.45 (dd, 0.1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[CH:27]=[CH:28][CH:29]=[C:20]([C:21]=23)[S:19]1(=[O:31])=[O:30].S1(=O)(=O)C2=CC=CC3=CC=CC(=C23)N1.BrCCCCBr>>[O:30]=[S:19]1(=[O:31])[C:20]2=[CH:29][CH:28]=[CH:27][C:26]3=[CH:25][CH:24]=[CH:23][C:22](=[C:21]23)[N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1
Reactant: NCC1CCc2ccccc2O1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCBr
Agent: O=S1(=O)Nc2cccc3cccc1c23
Solvent: BrCCCCBr
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCNCC1CCc2ccccc2O1

Procedure:
The compound is prepared from 2-aminomethyl-3,4-dihydro-2H-chromene and 2-(4-bromobutyl)-2H-naphth[1,8-cd]isothiazole 1,1-dioxide (available from 2H-naphth [1,8-cd]isothiazole 1,1-dioxide and 1,4-dibromobutane using a base) according to the working directions of
Reaction SMILES: [C:1]1([P:7](Cl)(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14])[OH:12].C(N(CC)CC)C>CCOCC>[C:1]1([P:7]2(=[O:8])[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1O
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P1(c2ccccc2)Oc2ccccc2O1
Reaction time: 0.13 h
Yield: 93.4 %

Procedure:
To a solution of 3.11 g of phenylphosphonic acid dichloride in 10 ml of ether were added 1.76 g of pyrocatechol and 20 ml of ether. The resulting solution was cooled to -25° C. to -28° C. and a solution of 3.23 g of triethylamine in 10 ml of ether was added dropwise thereto with stirring over 8 minutes. Thereafter, the reaction mixture was allowed to return to room temperature (20°-25° C.), and the precipitate was filtered off under nitrogen atmosphere and washed with 30 ml of ether. The filtrate and washings were combined and the ether was distilled off under reduced pressure to give 3.46 g (94.4% yield) of 2-phenyl-2-oxo-1,3,2-benzodioxaphosphole as a colorless oil. Upon standing in a refrigerator overnight, it crystallized.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=[O:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Temperature: 25 °C

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (15 mg, 0.022 mmol, 1.0 equiv) was dissolved in MeOH (437 μl). To this solution was added sodium borohydride (3.31 mg, 0.087 mmol, 4.0 equiv) and stirred at r.t. The solution turned to colorless immediately. It was stirred for ten minutes and quenched by water, extracted by Ethyl Acetate. The organic layer was concentrated to give the pure enough product for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][CH2:19][CH:18]1[C:25](O)=[O:26].C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:25]([CH:18]3[CH2:19][O:20][C:21]([CH3:23])([CH3:24])[CH2:22][N:17]3[CH3:16])=[O:26])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CN1CC(C)(C)OCC1C(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 61 %

Procedure:
The desired compound was prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 4,6,6-trimethyl-morpholine-3-carboxylic acid in 61% yield. 1H-NMR (DMSO-d6, 300 MHz) δ 1.15 (s, 3H), 1.39 (s, 3H), 1.98 (d, 1H), 2.26 (s, 3H), 2.72 (d, 1H), 2.80 (dd, 1H), 3.79(m, 2H), 7.91 (s, 1H), 8.03-8.08 (m, 2H), 8.22 (d, 1H), 8.97 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.33 min. MS (M+H+): 373.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([OH:13])=[CH:8][CH:7]=2)#[N:2].Br[CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17]>>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17])=[CH:8][CH:7]=2)#[N:2]
Reactant: N#Cc1cnc2ccc(O)cc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncc(C#N)cc2c1

Procedure:
In a similar procedure to Example 6 Stage 2, 3-cyano-6-hydroxyquinoline was reacted with 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide to give 2-(3-cyano-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide as a pale yellow solid, m.p. 116-118° C., 1H NMR (CDCl3) δ: 1.08(3H, t); 1.61(3H, s); 1.63(3H, s); 1.80(3H, s); 2.07-2.13(2H, m); 4.72(1H, t); 6.46(1H, s); 7.50 (1H, m); 7.57(1H, dd); 7.71(1H, d); 8.17(1H,d); 8.92(1H, d).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][OH:12])=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:13][C@@H:14]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:15])=[CH:4][CH:3]=1>C(OCC)(=O)C>[CH:11]([C:10]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH2:13][C@@H:14]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:15])[N:7]=[CH:6]2)=[O:12]
Reactant: C[C@@H](Cn1ncc2ccc(O)c(CO)c21)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](Cn1ncc2ccc(O)c(C=O)c21)NC(=O)OCc1ccccc1
Temperature: 47.5 °C
Reaction time: 48 h
Yield: 34.5 %

Procedure:
A solution of the compound from Step A (18.44 g, 0.0519 mol) in ethyl acetate (180 mL) was treated with mangenese dioxide (fine powder, 18 g) and stirred at 45-50° C. for two days. Then the reaction stood at room temperature one day. The mixture was filtered and the black solids were rinsed with ethyl acetate. The organic filtrate was evaporated to a tan foam. The residue was purified by chromatography (silica gel, hexane/ethyl acetate 1:1) to give the title compound, (6.32 g, 35%) as a pale yellow fluffy solid, which was pure by LS/MS 354 m/z.
Reaction SMILES: C(CN1CN(CC(OCC)=O)CN(CC(OCC)=O)C1)(OCC)=O.COC1C=CC(OP([O-])OC2C=CC(OC)=CC=2)=CC=1.COC1C=CC(O[C:52](OC2C=CC(OC)=CC=2)([P:60]([OH:63])([OH:62])=[O:61])[NH:53][CH2:54][C:55]([O:57]CC)=[O:56])=CC=1>Cl>[P:60]([CH2:52][NH:53][CH2:54][C:55]([OH:57])=[O:56])([OH:63])([OH:62])=[O:61]
Reactant: CCOC(=O)CNC(Oc1ccc(OC)cc1)(Oc1ccc(OC)cc1)P(=O)(O)O
Agent: CCOC(=O)CN1CN(CC(=O)OCC)CN(CC(=O)OCC)C1
Agent: COc1ccc(OP([O-])Oc2ccc(OC)cc2)cc1
Agent: Cl
Product: O=C(O)CNCP(=O)(O)O
Temperature: 80 °C

Procedure:
1,3,5-Tricarbethoxymethylhexahydro-1,3,5-triazine (5.76 parts) and di(4-methoxyphenyl)phosphite (15.3 parts containing 0.6 parts of 4-methoxyphenol) were mixed and heated to 80° C. for from 1/2 to 1 hour. Nuclear magnetic resonance spectral analysis indicated that a complete conversion to the ethyl N-[di(4-methoxyphenoxy)-phosphonomethyl]glycinate was obtained. The reaction mixture can then be diluted with 2 normal hydrochloric acid (225 ml) and heated to reflux for 2 hours. This reaction mixture is concentrated and then mixed with a mixture of water and methylene chloride. The water layer is then extracted with methylene chloride. The aqueous layer is concentrated to yield N-phosphonomethyl glycine.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[O:3]1.B(Cl)(Cl)Cl.CS[C:20]#[N:21].[Cl-].[Cl-].[Cl-].[Al+3].[OH-].[Na+]>ClC(Cl)C.O>[OH:12][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][C:2]([CH3:13])([CH3:1])[O:3]2)=[CH:8][C:7]=1[C:20]#[N:21]
Reactant: CC1(C)CCc2ccc(O)cc2O1
Reactant: CSC#N
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CC1(C)CCc2cc(C#N)c(O)cc2O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In a 250 mL round-bottom flask was placed 2,2-dimethyl-Chroman-7-ol (1.76 g, 9.87 mmol, from Step 4-1-2) in 30 mL of dry dichloroethane under argon. The solution was cooled to 0° C. where boron trichloride (10.8 mL, 1M in CH2Cl2, 10.8 mmol, 1.1 eq) was added dropwise. At this point, methyl thiocyanate (0.80 g, 10.8 mmol, 1.1 eq) was added followed by aluminum trichloride (1.32 g, 9.87 mmol, 1 eq). The reaction was allowed to warm up to rt and stirred for 17 h. The reaction mixture was cooled down to 0° C. and 10 mL of 50% w/w NaOH was added to adjust the solution to PH˜14, followed by 40 mL of water. The solution was then refluxed at 65° C. for 2 h. The solution was allowed to cool to ambient temperature. The aqueous layer was washed with dichloromethane (20 mL). The aqueous solution was transferred to an Erlenmeyer flask and acidified to pH˜1 with conc. HCl. This solution was then extracted with EtOAc (3×20 mL) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified on silica gel (flash column chromatography) eluting with 5% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide the desired product as white solid. The desired product was white solid (0.33 g, 16.5% ). 1H-NMR (CD3CN) δ 7.93 (broad s, 1H, OH), 7.26 (s, 1H), 6.28 (s, 1H), 2.69 (t, 2H), 1.80 (t, 2H), 1.32 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16](=O)[CH2:17]Br)=[C:11]([CH3:20])[CH:10]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]([NH2:24])=[S:23]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[N:21]=[C:22]([NH2:24])[S:23][CH:17]=3)=[C:11]([CH3:20])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2ccc(Br)cc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CC#N
Product: Cc1cc(Nc2ccc(Br)cc2)cc(C)c1-c1csc(N)n1
Yield: 73.5 %

Procedure:
A solution of 1-(4-(4-bromophenylamino)-2,6-dimethylphenyl)-2-bromoethanone (1.6 g, 4.0 mmol) and thiourea (0.79 g, 7.2 mmol) in acetonitrile (30 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give product (1.1 g), which was used directly for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26](=[O:34])[CH2:25][S:24]1.[CH3:35][C:36]([CH3:38])=O.N1CCCCC1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26](=[O:34])[C:25](=[C:36]([CH3:38])[CH3:35])[S:24]1
Reactant: CC(C)=O
Reactant: CCOC(=O)CN1C(=O)CSC1=Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(=C(C)C)SC1=Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of ethyl 2-{{2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl}imino}-4-oxo-3-thiazolidineacetate (2.0 g, 3.83 mmol), acetone (0.562 mL, 7.65 mmol), piperidine (0.20 mL, 2.02 mmol) and acetic acid (20 μL) in ethanol is refluxed for 90 minutes, treated with additional acetone (0.562 mL), refluxed for 3.5 hours, stirred at room temperature overnight, concentrated in vacuo, and chased with ethyl acetate to obtain a residue. Column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:3) gives the title product as a white solid (1.5 g, mp 67-80° C.).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][C:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:10]([NH2:16])[CH2:11][CH2:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+].Cl>[OH-].[Pd+2].[OH-].CO>[C:17]1([C@:9]23[NH:8][C@H:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][C@H:10]3[NH2:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CCC2CCC1(c1ccccc1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: N[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Temperature: 25 °C

Procedure:
To a 25 ml round bottom flask equipped with nitrogen inlet and condenser was placed 37 mg (0.127 mmol) of either the (1S,2S,5R) (or the (1R,2R,5S)) 8-Benzyl-1-phenyl-8-aza-bicyclo[3.2.1]oct-2-ylamine together with 10 ml of methanol, 80 mg (1.27 mmol) ammonium formate and 12 mg palladium hydroxide. The reaction mixture was treated with 21 ul of conc aq HCl and then heated under reflux for 40 mins and then cooled to room temperature. The suspension was filtered through a bed of celite which was then washed with methanol. The combined organics were evaporated in vacuo and the residue was taken up in chloroform and partitioned with saturated aqueous bicarbonate solution. The organics were washed with saturated brine solution and then dried over a bed of sodium sulfate. The mixture was filtered and the filtrate evaporated in vacuo to afford 20 mg of the desired (1S,2S,5R) (or the (1R,2R,5S)) diamine. 1H NMR (CDCl3, 400 MHz) δ 7.31–7.16 (br.m., 5H), 3.64–3.63 (br.s., 1H), 2.95 (dd, 1H, J=5 Hz, J=2 Hz), 2.25–2.19 (br.m., 1H), 2.03–1.89 (br.m., 2H), 1.87–1.78 (br.m, 5H), 1.72–1.66 (br.m., 1H), 1.54–1.49 (br.m., 1H), 1.33–1.28 (br.m., 1H) ppm. Mass spectrum APCI m/z 203 (p+1).