Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9].CO.C=O.[BH3-][C:42]#N.[Na+]>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:42])[N:15]=1)([CH3:10])[CH3:9]
Reactant: [BH3-]C#N
Reactant: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Reaction time: 0.33 h

Procedure:
To a solution of 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole and MeOH was added formaldehyde, followed by AcOH. The reaction was stirred for 20 min, NaCNBH3 was added to the reaction mixture and was continued to stir for another 30 min. After a routine aqueous work up, the crude product was purified by prep HPLC to give 2-[1-(2-chlorophenyl)-1-methylethyl]-4-(1-methylpyrrolidin-2-yl)-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazole: 1H NMR (CD3OD): δ 1.6 (m, 3H,), 1.8 (s, 1H), 1.9 (s, 3H), 2.2-2.5 (m, 4H), 2.8 (s, 3H), 3.2 (s, 3H), 3.6 (br, 1H), 4.7 (m, 1H), 7.1 (m, 1H), 7.2 (m, 5H), 7.4 (s, 1H), 7.7 (m, 3H), 8.0 (m, 2H), 8.2 (m, 1H); LC/MS M+H 534 (observed).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31])=[O:4])[N:6]=1)#[N:26]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Reactant: CC(C)(N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NC(C)(C)CC(=O)O)nc(C#N)c3c2)cc1
Yield: 21.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-amino-3-methyl-butyric acid (100 mg) and NaOMe (45 mg) in DMA (1.5 mL) was microwaved at 150° C. for 3 h. The mixture was cooled, diluted with water, acidified with 2 M HCl solution, solids were collected with filtration, washed with water, air dried then the residue was further column purified to give the desired product (27 mg). LC MS ESI+: 436 (M+1)+.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:34]=[CH:33][C:27]2[O:28][C:29]([F:32])([F:31])[O:30][C:26]=2[CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[F:32][C:29]1([F:31])[O:28][C:27]2[CH:33]=[CH:34][C:24]([CH:11]([C:12]3[C:20]4[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][C:26]=2[O:30]1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc4c(c3)OC(F)(F)O4)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc4c(c3)OC(F)(F)O4)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.37 g (5.76 mmol) of potassium cyanide was added to 1.35 g (2.88 mmol) of the compound from Example 112A in 26 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.90 g (78% of theory) of the target compound was obtained.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:12]Br>C(O)(=O)C>[Br:12][C:4]1[CH:3]=[N:2][N:1]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:5]=1
Reactant: BrBr
Reactant: c1cnc(-n2cccn2)nc1
Solvent: CC(=O)O
Product: Brc1cnn(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of 2-pyrazol-1-yl-pyrimidine (0.55 g, 3.7 mmol) in acetic acid (5 mL) was added bromine (1.2 g, 7.5 mmol) in acetic acid (3 mL) dropwisely. After addition, the reaction mixture was stirred at room temperature overnight. After removed the acetic acid, the crude product was purified using column chromatography (2% methanol in dichloromethane) to give 0.7 g of pure product in 85% yield. MS (ESMS, M+H 225).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20]CC4C=CC(OC)=CC=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cnc(NCc4ccc(OC)cc4)cc23)c1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cccc(Nc2ncnc3cnc(N)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To a stirred homogeneous solution of compound 167 (12.3 g, 32.3 mmol) in dry DCM (325 mL) was added trifluoroacetic acid (24.5 mL, 323 mmol), followed by anisole (7.11 mL, 64.6 mmol). The resultant mixture was stirred at room temperature for 70 h and then poured into petroleum ether (1 L) and stirred at room temperature for ca. 30 min. The petroleum ether layer was decanted and discarded. This process was repeated with more petroleum ether (800 mL). The residue left behind was dissolved in acetone/water (1:1, 200 mL) and stirred with 5M NH3 (500 mL) at room temperature for 1 h. The solid was collected by filtration and washed successively with acetone/water (1:4, 5×100 mL) and then petroleum ether/ethyl acetate (3:1, 5×100 mL) before being dried in vacuo to give N4-(3-ethynylphenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (169) (8.56 g, 98%), mp 220-225° C. (decomp); 1H NMR δ [(CD3)2SO] 9.69 (s, 1H), 8.70 (s, 1H), 8.38 (s, 1H), 8.08 (t, J=1.7 Hz, 1H), 7.95-7.89 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.34 (br d, J=7.7 Hz, 1H), 7.16 (s, 1H), 6.25 (s, 2H), 4.17 (s, 1H). Anal. Calcd for C15H11N5.2H2O.0.2CH3COCH3: C, 60.65; H, 5.29; N, 22.67%. Found C, 60.54; H, 5.01; N, 22.56%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:11]([N:9]1[C:8](=[O:15])[N:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[C:3]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:4]2=[N:10]1)[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)cc1
Reactant: COc1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(C)cc2)cc1
Temperature: 150 °C
Yield: 90.3 %

Procedure:
To a stirring, degassed mixture of 7-bromo-2-isobutyl-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.015 g, 0.04 mmol), 4-methoxyphenylboronic acid (0.026 g, 0.17 mmol), and tetrakis(triphenylphosphine)palladium (2.5 mg, 0.002 mmol) in dioxane (0.3 mL) at 20° C. was added K2CO3 (0.024 g, 0.17 mmol) in water (0.11 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 14 mg of the title compound as a yellow solid. MS: [M+H]+=389.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH3:12][NH:13][C:14](Cl)=[O:15]>C(C1C=CC=CC=1)(C)(C)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:14](=[O:15])[NH:13][CH3:12]
Reactant: CNC(=O)Cl
Reactant: Oc1ccc2ccccc2c1
Solvent: CC(C)(C)c1ccccc1
Product: CNC(=O)Oc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
72 parts by weight of β-naphthol are dissolved in 250 parts by weight of t-butylbenzene at 80° C. 46.7 parts by weight of methylcarbamyl chloride are passed into this solution over a period of 10 minutes while nitrogen is simultaneously bubbled through the solution. The reaction is complete after 15 minutes. The hot reaction solution is then cooled to 0° C. 83.5 parts by weight of β-naphthyl-N-methylcarbamate are precipitated, this being equivalent to a yield of 83% of theory. The melting point is 119° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]([O:10][CH2:11][CH2:12]CC(=O)C)(=[O:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([O:10][CH2:11][CH2:12][CH2:1][C:2]([CH3:5])=[CH2:3])(=[O:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)CCCOC(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CCCOC(C)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.3 %

Procedure:
Potassium tert-butoxide (9.4 g, 84 mmol) was added to a mixture of methyltriphenylphosphonium bromide (30 g, 84 mmol) in THF (300 ml), and the mixture was stirred at room temperature for 40 minutes. To the mixture a solution of 4-oxopentyl acetate (9.9 g, 68.8 mmol) in THF (30 ml) was gradually added dropwise while cooling in an ice-bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with diethyl ether twice. The extracts were combined, washed with brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford 4-methyl-4-pentenyl acetate (5.9 g, yield 60.4%) as a colorless oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2N(O)N=[N:7][C:5]=2C=1.CCN=C=NCCCN(C)C.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][N:33]([C:36]3[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][N:37]=3)[C:34]=2[OH:35])=[CH:26][CH:25]=1)#[N:23].CCN(C(C)C)C(C)C.C1(CCN)CC1.Cl>CN(C=O)C.CO.O>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][N:33]([C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH:7][CH2:5][CH2:4][CH:3]4[CH2:2][CH2:1]4)=[O:42])=[CH:38][N:37]=3)[C:34]=2[OH:35])=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCCC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCCC4CC4)cn3)c2O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Combined HOBT (66.2 mg, 0.490 mmol) and EDCI (94 mg, 0.490 mmol), a solution 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (100 mg, 0.327 mmol, in DMF (1 mL)) and Hunig's base (169 mg, 1.306 mmol) in DMF (1 mL). Then 2-cyclopropylethanamine (41.7 mg, 0.490 mmol) was added and the reaction was stirred at ambient temperature for 14 h. The reaction mixture was diluted with MeOH (2 mL) and water (3 mL) and acidified to pH 4 using 1 N HCl to give a solid which were collected by filtration and recrystallized from MeOH to give the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.01-0.14 (m, 2 H) 0.35-0.49 (m, 2 H) 0.68-0.81 (m, 1 H) 1.46 (q, J=7.07 Hz, 2 H) 3.27-3.43 (m, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 8.14 (d, J=6.32 Hz, 2 H) 8.34-8.79 (m, 4 H) 8.85-8.97 (m, 1 H) 13.53 (br. s., 1 H). MS m/z [M+H]+ 374.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([O:22][Si](C)(C)C)=[C:19]([CH3:21])[CH3:20]>[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:19]([CH3:21])([CH3:20])[C:18]([O:17][CH3:16])=[O:22])=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccc(Br)cc1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Br)cc1
Yield: 98.5 %

Procedure:
In a similar manner to Preparation 14, Step 2, the reaction of (4-bromophenyl)(phenyl)methanol (10 g, 38 mmol), and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (23.2 g, 133 mmol) in the presence of titanium tetrachloride (1M in DCM, 42 ml. 41.8 mmol) afforded methyl 3-(4-bromophenyl)-2,2-dimethyl-3-phenylpropanoate (13 g, 99% yield). LC/MS (m/z) 347.05, 349 [(M+1)+]; HPLC Rt: 4.18 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:22])=[CH:23][CH:24]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Product: O=C(c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1)N1CCOCC1
Yield: 69 %

Procedure:
As described in example 43h, 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (881 mg, 2.7 mmol) was converted, using morpholine instead of thiomorpholine 1,1-dioxide, to the title compound (738 mg, 69%) which was obtained as a white foam. MS: m/e=397.3 [M+H]+.
Reaction SMILES: FC1C=CC(C[N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=CC=1.[H-].[Na+].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1>CN(C)C=O>[N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[CH:40][C:31]=1[O:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:10]2[NH:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:24][CH2:23]1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2nc(OCCN3CCC(Nc4nc5ccccc5[nH]4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.5 Parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol and 135 parts of N,N-dimethyl-formamide were stirred at room temperature and 0.75 parts of a sodium hydride dispersion 50% were added. After stirring for one hour at room temperature, 2.5 parts of 2-chloroquinoline were added and the whole was stirred overnight at room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 4.3 parts (58%) of 1-[(4-fluorophenyl)-methyl[-N-[1-[2-(2-quinolinyloxy)ethyl]- 4-piperidinyl]-1H-benzimidazol-2-amine; mp. 149.9° C. (compound 77)
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[NH4+].[SH:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21].ClC(Cl)(Cl)C(O)=O>O>[NH4+:6].[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[NH:6][CH:7]([S:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21])[CH2:1][CH2:2][O:3]1
Reactant: O=S(=O)([O-])CCS
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH4+]
Solvent: O
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 72 h

Procedure:
2.8 g (10 mmol) of 4-hydroxycyclophosphamide and 1.6 g (10 mmol) of ammonium-2-mercaptoethanesulphonate were dissolved together with a catalytic quantity of trichloroacetic acid in 50 ml of water and were left to stand in a refrigerator for 3 days at 0° C. The water was then distilled off under high vacuum, the residue was taken up twice in acetone and concentrated under vacuum. Recrystallisation from acetone/ether.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][CH:23]([CH2:26][CH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[CH2:24][OH:25].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[OH:31][C:29]([CH3:30])([CH3:32])[CH2:28][CH2:27][CH2:26][C@H:23]([CH3:22])[CH:24]=[O:25]
Reactant: CC(CO)CCCC(C)(C)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](C=O)CCCC(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
Pyridinium dichromate (1.5 g, 3.75 mmol) was added to a stirred solution of diol 8 (110 mg, 0.69 mmol) and pyridinium p-toluenesulfonate (33 mg, 0.11 mmol) in CH2Cl2 (5 mL). The resulting suspension was stirred for 4 hours at room temperature under argon. The reaction was then filtered through Celite and solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using hexane/EtOAc (9:1) as an eluent to give an oily aldehyde 9 (65 mg, 60%).
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[CH2:36]([C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(Cc2ccccc2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid ethyl ester (2.30 mmol) in THF (15 mL) and methanol (30 mL) was treated with 2.5N aqueous NaOH (10 mL). The solution was heated at 55° C. for 2 h, cooled to ambient temperature, and concentrated in vacuo. The residue was acidified with 5N aqueous HCl (5 mL) and partitioned between ethyl acetate (125 mL) and H2O (25 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to a give 2-{2-benzyl-4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ8.03-8.05 (m, 2H), 7.68 (d, 2H, J=8.3 Hz), 7.62 (d, 2H, J=6.8 Hz), 7.46 (t, 2H, J=7.3 Hz), 7.30-7.38 (m, 1H), 7.23-7.27 (m, 2H), 7.18 (d, 1H, J=7.3 Hz), 7.14 (d, 2H, J=8.3 Hz), 6.78 (d, 1H, J=9.3 Hz), 6.70 (d, 1H, J=2.9 Hz), 6.66 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 4.16 (t, 2H, J=6.4 Hz), 3.92 (s, 2H), 3.00 (t, 2H, J=6.4 Hz), 2.38 (s, 3H), 1.45 (s, 6H), MS (ES) m/e 554.2 (M+1).
Reaction SMILES: [Ca].[C:2]([O:6][C:7]([NH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[CH3:26][N:25]([CH3:27])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:13][CH2:14][C@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:5])([CH3:3])[CH3:4])[CH2:11]2)=[CH:21][CH:20]=1)(=[O:23])=[O:24]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Ca]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0° C., and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and disopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide. (2) In 600 ml of DMSO were suspended 25 g of (S)-(+3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassium carbonate, and the mixture was stirred at 130° C. for 1 day. To the reaction mixture were added water and ethyl acetate, the resulting mixture was stirred and the liquids were separated. The organic layer was washed with water, and then dried, and the solvent was evaporated. The residue was dissolved in chloroform, NH silica gel was added thereto and the mixture was allowed to stand for a while, and silica gel was filtered off. The silica gel was further washed with ethyl acetate. The filtrate and the washed solution were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(Cl)Cl>C(O)C>[CH2:1]([O:8][C:9](=[O:36])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCCc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1)OCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: NCCCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 206.4 %

Procedure:
A solution containing 59 (4.0 g, 8.20 mmol) and hydrazine (2.06 g, 41.20 mmol) dissolved in ethanol (50 mL) and methylene chloride (10 mL) was heated to reflux. The reaction mixture was allowed to stir for 16 h under N2 atmosphere. The solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0-20% (10% concentrated ammonium hydroxide in methanol) and dichloromethane to afford the desired product 7 (6.00 g, 72%) as an off white solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 4H), 7.07 (s, 4H), 5.08 (s, 2H), 3.18 (t, 2H), 2.94 (s, 2H), 2.70 (t, 2H), 2.59 (t, 4H), 1.65-1.47 (m, 5H); m/z (ESI) 355 [C22H30N2O2+H]+.