Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>O.CN(C=O)C>[Br:1][C:2]1[C:3]([C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Br
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ncccc1Br)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round-bottomed flask that had been purged with nitrogen, were added 3-bromopicolinic acid (500 mg, 2.50 mmol), morpholine (259 mg, 3.00 mmol), EDCI (712 mg, 3.70 mmol), HOBT (501 mg, 3.70 mmol), triethylamine (1.0 mL, 7.4 mmol) and DMF (12 mL). The mixture was stirred at rt for 24 h, before diluting with water (100 mL) and extracting with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated bicarbonate (1×50 mL), water (2×50 mL), dried with sodium sulfate, and concentrated to dryness. The crude product was purified by FCC to provide the title compound. MS (ESI): mass calcd. for C10H11BrN2O2, 270.00; m/z found, 271.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.57 (dd, J=4.7, 1.4, 1H), 7.93 (dd, J=8.2, 1.4, 1H), 7.23 (dd, J=8.2, 4.7, 1H), 3.90-3.77 (m, 4H), 3.74-3.62 (m, 2H), 3.30-3.15 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[CH3:30][NH2:31].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[CH3:30][NH:31][S:15]([CH2:14][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:17])=[O:16].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol, 1.0 eq.) in DCM (1.0 mL) was combined with a solution of methylamine (2M in THF; 4.0 eq) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (8.7 mg). MS m/z: [M+H]+ calcd for C14H19F3N2O3S, 353.11. found 353.0.
Reaction SMILES: [Li]CCCC.CCCCCC.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[C:21]3[CH:27]=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1.CN(C1C=CN=CC=1)C>[C:29]([Si:32]([CH3:34])([CH3:33])[N:25]1[C:22]2=[N:23][CH:24]=[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)[CH:20]=[C:21]2[CH:27]=[CH:26]1)([CH3:31])([CH3:30])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1cccc(-c2cnc3[nH]ccc3c2)c1
Agent: CN(C)c1ccncc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccc(F)c3)cnc21
Yield: 80.6 %

Procedure:
2.5 M solution of n-BuLi in hexane (13.7 mL, 34.3 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of azaindole 7 (6.04 g, 28.5 mmol) in THF (30 mL). After the mixture was stirred for 10 min at −78° C., DMAP (66 mg, 0.54 mmol) was added, followed by a solution of TBSCl (5.14 g, 34.1 mmol) in THF (2.5 mL). The mixture was stirred at −78° C. for 1 h. Cooling bath was removed, the mixture was stirred at r.t. for 3 days, and separated between AcOEt:saturated aqueous NaHCO3 solution. The aqueous layer was extracted with AcOEt (3×). Combined organic solutions were dried (MgSO4), concentrated, and separated by means of SGC with hexane:benzene as eluent in gradient (up to 15% benzene) to afford 8 (7.50 g, 81%) as white solid. 1H NMR (400 MHz, CDCl3) δ 0.67 (s, 6H), 0.96 (s, 9H), 6.59 (d, J=3.5 Hz, 1H), 6.99-7.07 (m, 1H), 7.29 (d, J=3.5 Hz, 1H), 7.33 (ddd, J=10.9, 3.0, 1.7 Hz, 1H), 7.38-7.44 (m, 2H), 8.04 (d, J=2.3 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(C)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(CC(C)C)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 33.1 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (635 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.82 ml) and 1-methyl-2-chloropyridinium iodide (1 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-4-methylpentanamide (455 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]1.[CH3:10]C1NN=C(N)C=1>>[CH3:10][C:5]1[NH:1][N:2]=[C:3]([NH:6][C:7](=[O:9])[CH3:8])[CH:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(=O)Nc1cc[nH]n1
Product: CC(=O)Nc1cc(C)[nH]n1
Yield: 70.4 %

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 1, replacing 1H-pyrazol-3-amine with 5-methyl-1H-pyrazol-3-amine. (ALDRICH, 1.01 g, 7.25 mmol, 70.4% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.89 (s, 1H), 10.16 (s, 1H), 6.22 (s, 1H), 2.16 (s, 3H), 1.94 (s, 3H). [ES+MS] m/z 140 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>O1CCOCC1.CCOC(C)=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: NCC(O)CO
Reactant: N#Cc1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NCC(O)CO)nc1
Temperature: 80 °C

Procedure:
A mixture of 3-amino-1,2-propanediol (4.93 g, 54.1 mmol) and 6-chloronicotinonitrile (1.50 g, 10.8 mmol) was prepared in anhydrous dioxane (20 mL), and then stirred at RT for hours and 80° C. for additional hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with a half saturated solution of brine (2×50 mL) and brine (50 mL). The aqueous layers were extracted with EtOAc (2×50 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by trituration in hot MTBE (10 mL) and filtration, the title compound was obtained as a white powder (970 mg, 46%). UPLC/MS, M+(ESI): 193.9, M−(ESI): 192.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2)([O-:3])=[O:2].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:9]=[C:10]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)cc2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of ethyl 7-nitro-1H-indole-2-carboxylate (2.00 g, 8.45 mmol) in N,N-dimethylformamide (50 ml) was added 60% sodium hydride (0.34 g, 8.54 mmol), and the reaction mixture was stirred at room temperature until it became transparent. Then, ethyl bromoacetate (1.43 g, 8.54 mmol) was added and the resulting mixture was stirred at 50°-60° C. for 4 hours. The reaction mixture was cooled to room temperature and poured into ice water, followed by extraction with ethyl acetate (three times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/95) to obtain ethyl 1-ethoxycarbonylmethyl-7-nitro-1H-indole-2-carboxylate (2.11 g).
Reaction SMILES: [Br:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.[Cl:33]CCl>>[Br:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:33])=[CH:7][CH:6]=1
Reactant: Oc1ccc(C#CCBr)cc1
Reactant: ClCCl
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C#CCBr)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a solution of 4-(3-bromo-prop-1-ynyl)-phenol (5.0 g, 30.12 mmol) dissolved in dichloromethane, 8.3 g (31.63 mmol, 1.05 eq) of triphenylphosphine was added and the solution was cooled to 0° C. Bromine (1.55 mL, 30.12 mmol, 1.0 eq) was added dropwise and the reaction was warmed to room temperature. The reaction was then diluted with dichloromethane, washed with sodium hydrosulfite pentahydrate, washed with brine, dried over MgSO4 and concentrated. The residue was purified via flash chromatography using 4:1 hexane:ethyl acetate to afford 5.56 g (80%) of 1-(3-bromo-prop-1-ynyl)-4-chloro-benzene as an amber oil. Electrospray Mass Spec 280.4 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23](O)=[O:24])(=[O:17])=[O:16].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([NH:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][N:10]=1)=[O:24])(=[O:17])=[O:16]
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1nnc(-c2ccc(F)cc2)s1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Cl)c(C(=O)Nc2nnc(-c3ccc(F)cc3)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 ml scintillation vial containing a Teflon covered magnetic stir-bar was added commercially available 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (25 mg, 0.128 mmol) and 5-(aminosulfonyl)-2-chlorobenzoic acid (22.3 mg, 0.128 mmol). To this mixture was added EDC (25 mg, 0.128 mmol) and HOAt (18 mg, 0.128 mmol) followed by 3 ml of DCM. The resulting mixture was stirred at room temperature overnight. The product precipitated and was collected by vacuum filtration, washed with 3 ml of MeOH and air-dried under vacuum. Yield of 5-(aminosulfonyl)-2-chloro-N-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzamide was (7 mg) as a white powder.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[O:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>>[F:30][C:28]1[CH:27]=[CH:26][C:25]2[C:21]([CH2:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C@H:12]4[N:8]5[C:9]6[C:4](=[CH:3][CH:2]=[CH:1][C:10]=6[C@H:11]4[CH2:16]3)[CH2:5][CH2:6][CH2:7]5)=[N:22][O:23][C:24]=2[CH:29]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc2c(CCCN3CC[C@@H]4[C@H](C3)c3cccc5c3N4CCC5)noc2c1
Yield: 31.9 %

Procedure:
The title compound (0.15 g, 32%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (0.43 g, 2.0 mmol), KI (catalytic) and K2CO3(0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.80–2.18 (m, 7H), 2.25 (td, J=11.5, 3.0 Hz, 1H), 2.35–2.68 (m, 4H), 2.70 (t, J=6.6 Hz, 2H), 2.75–2.88 (m, 1H), 3.01 (t, J=7.6 Hz, 2H), 3.05–3.15 (m, 1H), 3.20–3.30 (m, 2H), 6.62 (t, J=7.5 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 7.06 (td, J=9.0, 2.1 Hz, 1H), 7.20–7.26 (m, 1H), 7.61 (dd, J=4.8, 8.7 Hz, 1H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:17]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:42].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:16]=[C:17]([C:35]3[N:36]=[CH:37][CH:38]=[CH:39][N:40]=3)[N:18]=[C:19]([O:30][CH2:31][CH2:32][C:33]([OH:42])=[O:34])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCO
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
To a solution of 4-t-butyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (3.2 g) in dimethylformamide (50 ml) was added pyridinium dichromate (31.9 g). The mixture was stirred for 12 hours at room temperature, and subsequently supplemented with pyridinium dichromate (10.6 g), followed by stirring for 12 hours. Ethyl acetate was added, and the mixture was washed with 1N-HCl and then with water. The organic layer was extracted with sat. aq. NaHCO3, and the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with dilute HCL, and then extracted with ethyl acetate. The organic layer was washed with saturated brine. Drying over anhydrous magnesium sulfate and concentrating under reduced pressure gave 1.85 g of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionic acid as a pale yellow powder.
Reaction SMILES: [Br:1]Br.[Cl-].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH2:13][P+:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[Br-:1].[Br:1][C:10]1[C:5]([OH:4])=[C:6]([CH2:13][P+:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=1
Reactant: BrBr
Reactant: COc1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Solvent: CO
Product: COc1cc(Br)c(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Reaction time: 2 h
Yield: 76 %

Procedure:
In the course of 1.5 hours, at 5°, 13 g of bromine are added dropwise to a solution of 35 g of [(2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride in 700 ml of methanol. The solution is concentrated in vacuo at 20° to 110 ml, 220 ml of ethyl acetate are added thereto in the course of 2 hours, the resulting yellow suspension is stirred for 2 hours at 0°, and the slightly yellow crystals are filtered off with suction and recrystallised from methanol. A mixture of colourless crystals (m.p.: 210°) which according to AgNO3 titre comprises 22.4 percent by weight [(3-bromo-2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium chloride and 77.6 percent by weight [(3-bromo-2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium bromide is obtained; yield 76% of the theoretical yield.
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH2:10][NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[CH:7][CH:6]=1.Cl>C(O)=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][N:11]([C:12]([CH3:15])([CH3:16])[CH2:13][OH:14])[CH3:1])=[CH:17][CH:18]=1
Reactant: COc1ccc(CCNC(C)(C)CO)cc1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: COc1ccc(CCN(C)C(C)(C)CO)cc1
Yield: 89.9 %

Procedure:
37% Aqueous formaldehyde solution (2.68 g) was added to a stirred solution of 2-(4-methoxyphenethylamino)-2-methylpropanol (3.35 g -- see Preparation 6) in formic acid (3.45 g) and the mixture was heated under reflux for 2.5 hours, acidified with 2M hydrochloric acid, washed with ether, basified with solid sodium hydroxide and extracted into ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was triturated with hexane to give the title compound as a colourless solid (3.20 g, 90%), m.p. 40°.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13]([NH:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:13]([NH:21][C:22]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[CH2:26][CH2:25]1)=[O:30])(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=C(NC(=O)c1ccccc1)NC1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2cccc3ccccc23)CC1

Procedure:
1-Chloromethylnaphthalene (0.88 g, 0.005 m), 4-benzoylureidopiperidine (1.28 g, 0.005 m) and triethylamine (0.6 g) in dimethylformamide (25 cm3) were stirred at room temperature for 24 hours. Water was added and the precipitated solid filtered off. The solid was suspended in isopropylalcohol and acidified with ethanolic HCl. The title compound was filtered off and dried as the hydrochloride salt, hemihydrate (1.2 g), m.p. 185°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([O:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21])[C:16](O)=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.CCN(C(C)C)C(C)C.C(N=C=NC(C)C)(C)C>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[C@@H:20]([O:19][C@H:15]([C:16](=[O:17])[NH:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:21])[CH3:26]
Reactant: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: Nc1nnn[nH]1
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)O[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethoxy)-propionic acid (62 mg, 0.165 mmol) in THF (5 ml) at room temperature was added 5-aminotetrazole (38.0 mg, 0.447 mmol), DIPEA (0.086 ml, 0.494 mmol) and followed by 1,3-diisopropylcarbodiimide (0.060 ml, 0.387 mmol). The reaction was stirred at room temperature for 3 hr. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. HPLC retention time=0.99 minutes (condition C); MS (m+1)=444.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:13][C:14]1[CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=[C:18]([F:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:21][O:22][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OCc1cc(F)cc(F)c1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(OCc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 5-fluoro-2-nitrobenzonitrile (60 g, 354 mmol), (3,5-difluorophenyl)methanol (52.14 mL, 460 mmol) and cesium carbonate (155 g, 460 mmol) in dry DMF (720 mL) was stirred at 70° C. for 6 hours. The reaction mixture was cooled at room temperature and poured into water (7 L) under stirring. The so obtained precipitated was filtered, washed with water and dried under vacuum at 50° C., affording 95 g (yield 92%) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([CH:13]2OCC[O:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:8]1[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2ccc(C3OCCO3)o2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1ccc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
The resulting 2-(5-benzyl-furan-2-yl)-[1,3]dioxolane (3.8 g, 16.5 mmol) was suspended in a mixture solution of methanol (15 mL), tetrahydrofuran (10 mL) and 2N hydrochloric acid (15 mL), and the solution was stirred at room temperature for 2 hours. Ethyl acetate and an aqueous solution of sodium bicarbonate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice and dried over anhydrous sodium sulfate. The solvent was evaporated, and the title compound (2.5 g, 13 mmol) was obtained as a brown oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1O.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([F:19])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C.C([OH:32])(C)C>>[Cl:11][C:12]1[N:17]=[C:16]([NH:2][CH2:3][C:4]2([OH:32])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[C:15]([F:19])=[CH:14][N:13]=1
Reactant: NCC1CCCCC1O
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: OC1(CNc2nc(Cl)ncc2F)CCCCC1
Temperature: 80 °C

Procedure:
To a solution of 2-(aminomethyl)cyclohexanol hydrochloride (0.09 g, 0.54 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.10 g, 0.60 mmol) in isopropanol (2 mL) was added iPr2NEt (0.21 mL, 1.20 mmol). The reaction mixture was heated at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (25%-75% EtOAc/hexanes) to afford desired product, 14a.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[N:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH:12]1[CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1CCCCC1>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][C@@H:12]1[CH3:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(=Nc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CC(=O)O
Solvent: O
Product: C[C@H]1C[C@@H](Nc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
To a solution of 2-methyl-4-phenylimino-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (16 g) in acetic acid (450 ml), sodium triacetoxyborohydride was added in small amounts (32.32 g), under stirring, at room temperature. The reaction mixture was then stirred at room temperature for one hour and poured on 1 liter of cold water under stirring. After precipitation, the mixture was filtered, dissolved in ethyl acetate and then, washed with water. The organic layer was separated and dried over sodium sulfate. The solvent was removed to give the crude compound (9g), recristallised in hot cyclohexane (40 ml), and then filtered at room temperature to give the desired compound (5.3 g, 46.6% yield).