Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CC(OC)(C)C>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:23])=[O:2])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](CSc1ccc(Br)cc1N)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CSc1ccc(Br)cc1N)C(=O)O
Yield: 100 %

Procedure:
19.9 g (48.02 mmol) of N-tert-butoxycarbonyl-3-(2-amino-4-bromophenylthio)-L-alanine methyl ester (97.8%) was dissolved in 750 ml TBME and emulsified in 3 L buffer solution (0.1M sodium chloride, 20 mM sodium phosphate pH 7.5) under vigorous stirring. 12.0 ml Alcalase 2.4 L and 30 mg Substilisin A [both enzyme preparations are subtilisin Carlsberg from Novo Nordisk] were added and the pH was maintained at 7.5 under vigorous stirring by the controlled addition (pH-static) of 1.0N sodium hydroxide solution. After 7d 44.75 ml of 1.0N sodium hydroxide solution was consumed and the conversion degree was >99% (HPLC analysis). The biphasic reaction mixture was separated. The aqueous phase was washed briefly with 1 L TBME for the separation of small amounts of lipophilic impurities and traces of the remaining substrate. The combined organic phases were extracted with 1×250 ml 0.1 M potassium phosphate buffer pH 7.6. The combined aqueous phases were acidified to pH 2 with 32% hydrochloric acid and extracted with 1.5 L ethyl acetate. The resulting emulsion was separated by the addition of 10% Dicalite under stirring and a subsequent filtration. The aqueous phase was extracted with 2×1 L ethyl acetate. The combined ethyl acetate phases were dried on anhydrous sodium sulfate and evaporated. The residue was dissolved in dichloromethane, evaporated and dried at HV to give 18.79 g N-tert-butoxycarbonyl-3-(2-amino-4-bromophenylthio)-L-alanine as a pale yellow solid (yield: 81.8%). Analytical data: 1H-NMR (CDCl3, 400 MHz) 1.399 (s, 9H, OC(CH3)); 3.184 (dd, 1H, SCH2, J=14.2 Hz, J=6.6 Hz); 3.235 (dd, 1H, SCH2, J=14.2 Hz, J=6.6 Hz); 4.515 (m, 1H, COCHNH); 5.517 (d, 1H, CONHCH, J=6.8 Hz); 6.796 (dd, 1H, arom., J=2 Hz, J=8.4 Hz); 6.876 (d, 1H, arom., J=2 Hz); 7.250 (d, 1H, arom., J=8.4 Hz). IR (ATR-IR) 3445 and 3355 cm−1 (—NH, —NH2); 2978 and 2929 cm−1 broad (—COOH); 1693 cm−1 (COOH —C═O, carbamate —C═O); 1508 cm−1 (amide —CO—NH); 1247 and 1157 cm−1 (COOH). MS (ESI-positive ionization) m/z=391.1 [M+H+] with 79Br; m/z=393.1 [M+H+] with 81Br; m/z=413.2 [M+Na+] with 79Br; m/z=415.2 [M+Na+] with 81Br. OR [α]D=+53.3° (CHCl3; c=1.0). HPLC analysis: column: ABZ+plus; mobile phase: A: 0.1% TFA in H20; B: MeCN; gradient B: 30–80% 0–15 min, 80–30% 15–16 min, 30% 16–19.5 min; flow:1 ml/min; pressure: 50–80 bar; detection: UV, 300 nm; retention times: 12.1 min (product-acid) 13.5 min (substrate-ester).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([C:24]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCO)c(C)c3)nc2c1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (1.3 g, 6.63 mmol) and 4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde (1.38 g, 6.63 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (1.30 g, 7.3 mmol), and p-TSA (252 mg, 1.32 mmol) were added and the reaction mixture was heated at 115° C. for 26 hours, then cooled to room temperature. The solvent was removed under reduced pressure. Then, water (100 mL) was added and stirred for 1 hour at room temperature. The separated solids were filtered and dried. The solids were again washed with diethyl ether to give crude product 2-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.69 g (66%).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:14][C:15]1([CH3:24])[C:18](=[C:19]([CH3:21])[CH3:20])[CH2:17][C@H:16]1[CH2:22]O.N1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C.CN(C=O)C.CO>[CH3:1][C@@H:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:22][C@@H:16]1[CH2:17][C:18](=[C:19]([CH3:21])[CH3:20])[C:15]1([CH3:24])[CH3:14])=[O:4]
Reactant: CC[C@H](C)C(=O)O
Reactant: CC(C)=C1C[C@@H](CO)C1(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC[C@H](C)C(=O)OC[C@@H]1CC(=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a solution of 2.2 mL (20.1 mmol) of (S)-(+)-2-methylbutanoic acid {Aldrich, 99% ee, [α]24D+24.0 (c 0.1, MeOH)} in 15 mL of benzene was treated with 2.2 mL (25.2 mmol) of oxalyl chloride and 10 μl of DMF. After 1.5 h at room temperature, the benzene and excess oxalyl chloride were removed followed by the addition of another 15 mL portion of benzene. The acid chloride residue was dissolved in 15 mL of benzene, and then a solution of 1.65 g (10.7 mmol) of 6a and 18 ml (22.2 mmol) of pyridine in 15 mL of benzene were added dropwise. After stirring at room temperature for 1 h, the solvent was removed. The residue was treated with 20 mL of water, and extracted with ether. The organic solution was washed with water, 1N hydrochloric acid, 1N aqueous sodium bicarbonate, and brine, dried over sodium sulfate, and concentrated to afford yellow oil. Pure 2a (2.0 g, 79% yield) was obtained by chromatography (silica gel, 2% of ethyl acetate in hexanes). Optical purity: 99% ee; [α]24D−0.79 (c 2.03, MeOH); 1H NMR (C6D6): δ 0.84 (3H, t, J=7.19 Hz), 1.08 (3H, d, J=6.82 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.36 (1H, m), 1.40 (3H, bs), 1.51 (3H, t, J=1.89 Hz), 1.67 (2H, m), 2.05 (1H, m), 2.17 (1H, m), 2.27 (1H, m), 2.48 (1H, ddt, J=14.75, 8.79, 1.52 Hz), 4.15 (2H, d, J=7.57 Hz); 13C NMR (C6D6): δ 175.76, 137.48, 122.55, 65.30, 44.43, 41.39, 39.71, 28.62, 27.79, 27.13, 21.17, 19.60, 18.64, 16.85, 11.80; EI-MS m/z (%): 238 [M]+ (2), 136 (29), 121 (100), 107 (12), 93 (20), 81 (26), 67 (5), 57 (16), 41 (10); HREIMS: obsd. 238.1929, calcd. for C15H26O2 (M+): 238.1933.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:14]=[C:15]([NH2:22])[C:16](=[CH:20][CH:21]=1)[C:17](O)=[O:18]>>[F:11][C:12]([F:23])([F:24])[C:13]1[CH:14]=[C:15]2[C:16]([C:17](=[O:18])[N:6]3[C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[NH:3][C:2]3=[N:22]2)=[CH:20][CH:21]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: Clc1nc2ccccc2[nH]1
Product: O=c1c2ccc(C(F)(F)F)cc2nc2[nH]c3ccccc3n12

Procedure:
3-Trifluoromethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 4-trifluoromethyl-anthranilic acid.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:5]=1)(=O)[CH3:2].Cl.CN.[C:29]([BH3-])#[N:30].[Na+]>CO.C(OCC)(=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([C:6]2[CH:5]=[C:4]([CH:1]([NH:30][CH3:29])[CH3:2])[CH:15]=[CH:14][C:7]=2[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:21]=[CH:20][CH:19]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)COc1ccc(C(C)=O)cc1-c1cccc(C(F)(F)F)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(C)c1ccc(OCC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 108.9 %

Procedure:
To a solution of methyl 2-(4-acetyl-2-(3-trifluoromethylphenyl)phenoxy)acetate (17) (529 mg, 1.5 mmol, 1 eq) in MeOH (5 mL) was added methylamine hydrochloride (603 mg, 9.0 mmol, 6 eq) and sodium cyanoborohydride (93 mg, 1.5 mmol, 1 eq). The reaction mixture was stirred at room temperature for 8 days, diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated in vacuo to give crude compound methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(methylamino)ethyl)phenoxy)acetate (18) as white solid (600 mg) which was carried directly to the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][S:7]([C:10]1[S:14][C:13]([NH:15]C(=O)C)=[N:12][C:11]=1[CH3:19])(=[O:9])=[O:8])([CH3:5])[CH3:4]>Cl>[OH:1][CH2:2][C:3]([NH:6][S:7]([C:10]1[S:14][C:13]([NH2:15])=[N:12][C:11]=1[CH3:19])(=[O:9])=[O:8])([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)CO)s1
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Temperature: 80 °C
Yield: 71.6 %

Procedure:
A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (1.15 g, 3.58 mmol) in 6N hydrochloric acid (14 ml) was heated for 2 h at 80° C., evaporated., and saturated NaHCO3 solution (30 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) to yield the title compound (0.68 g, 71%) as a white solid. MS (ISP) 264.0 [(M−H)−]; mp 146° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19](O)=[O:20])=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:20])=[C:14]([C:16]([NH2:17])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)C1CC(C1)c1ccc(Br)cc1-2
Reactant: CC(C)N
Product: CC(C)NC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1ccc(Br)cc1-2
Yield: 99 %

Procedure:
10-bromo-2-carbamoyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-3-carboxylic acid was reacted with isopropylamine similarly to as described in example 2 with non-critical modifications to afford 166 mg (99%) 10-bromo-N3-isopropyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. 10-bromo-N3-isopropyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 43 mg (23%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-isopropyl-5,6,7,12-tetrahydro-5,7-methanobenzo [c]imidazo[1,2-a]azepine-2,3-dicarboxamide.
Reaction SMILES: I[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[S:60]1[C:68]2[CH:67]=[CH:66][N:65]=[CH:64][C:63]=2[N:62]=[CH:61]1>CS(C)=O.C(OCC)(=O)C>[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:29](=[N:55]/[O:56][CH3:57])/[C:28]([NH:27][CH:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][N+:65]4[CH:66]=[CH:67][C:68]5[S:60][CH:61]=[N:62][C:63]=5[CH:64]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1
Reactant: c1cc2scnc2cn1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4scnc4c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate [VIIa] (1.50 g, 1.61 mmoles) and thiazolo[4,5-c]-pyridine (300 mg, 2.20 mmoles) in dry dimethylsulfoxide (DMSO) (7.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (5 mL), dried and evaporated to dryness. To a solution of the residue in CHCl3 (5 mL) was added ether (50 mL) to give the quaternized blocked cephalosporin [XIIIa] (1.7 g), which was collected by filtration and treated with 90% trifluoroacetic acid [TFA] (17 mL) at room temperature for 1 hour. After evaporation of the solvent, the residue was triturated with ether, filtered and dissolved in CH3OH (2 mL). The solution was treated with 1M sodium 2-ethylhexanoate [SEH] in ethyl acetate (3.2 mL) at room temperature for 30 minutes to afford 774 mg of the crude title compound (Ia), which was purified by HPLC (Column, Lichrosorb RP-18, 8×300 mm; eluted with 0.01M ammonium phosphate buffer, pH 7.2--15% CH3OH) and HP-20 column chromatography (3×30 cm, washed with 1 L of water and eluted with 700 mL of 30% CH3OH). The fractions containing the desired product were collected, concentrated and lyophilized to afford 180 mg (22%) of the title compound (Ia) as a colorless powder, mp 165° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:29])[C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]2[C:19]=1[OH:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1c(OC)ccnc1Cl
Product: CCOC(=O)c1oc2nccc(OC)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 4-methoxy-2-chloronicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([Cl:25])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.[CH:26]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([Cl:25])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:30]([CH:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(Oc3c(Cl)cc(F)cc3Cl)CC2)CC1
Reactant: O=C(O)C1CCC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3c(Cl)cc(F)cc3Cl)CC2)CC1)C1CCC1

Procedure:
According to the synthesis of example 1 the title compound was prepared from Trans(4-{2-[4-(2,6-dichloro-4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amine and cyclobutanecarboxylic acid. Preparative HPLC on reversed phase eluting with acetonitrile/water yielded the title compound. MS (m/e): 471.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[C:7]=1[Cl:14].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:26]1([N:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:33](=[O:34])[N:32]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]=1[Cl:14]
Reactant: COC(=O)COc1cccc(CO)c1Cl
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(COC(=O)N(c2ccccc2)c2ccccc2)c1Cl
Temperature: -78 °C
Yield: 48 %

Procedure:
A solution of (2-chloro-3-hydroxymethylphenoxy)acetic acid methyl ester (1.94 g, 8.41 mmol) in tetrahydrofuran was cooled to −78° C., treated with potassium bis(trimethylsilyl)amide (10.1 mmol), and allowed to stir at −78° C. for about an hour. A solution of diphenylcarbamyl chloride (2.92 g, 12.6 mmol) in tetrahydrofuran was added dropwise, and the resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water, diluted with diethyl ether, and the layers were separated. The aqueous layer was extracted twice more with diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by silica gel flash chromatography, eluting with hexane/acetone (4:1), gave {2-chloro-3-[(diphenyl-carbamoyloxy)methyl]phenoxy}acetic acid methyl ester as a white crystalline solid (1.72g, 48.0%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][CH3:12])=[O:9])[CH:20]=[CH2:19]
Reactant: CCOC(=O)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1C(=O)OCC
Yield: 98.3 %

Procedure:
To a solution of ethyl salicylate (100 g, 0.602 mol) in DMF (400 ml) was added K2CO3 (150 g), followed by the dropwise addition of allyl bromide (87.5 g, 0.723 mol). The reaction mixture was then heated on a steam bath for 2 hours, the K2CO3 was removed by filtration and the reaction mixture was poured into water and extracted with ethyl acetate (3×300 ml). The organic layer was washed with brine, and dried over MgSO4, and the solvent was removed to afford 122 g (98%) of ethyl 2-(2-propenyloxy)benzoate.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:17]=1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][C:15]1[S:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[N:17][CH:16]=1
Reactant: COC(=O)CCc1cnc(C2CCCN2C(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCc1cnc(C2CCCN2)s1

Procedure:
A solution of 2-[5-(2-Methoxycarbonyl-ethyl)-thiazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.37 g, 1.09 mmol) in a solution of hydrochloric acid in dioxane (4N, 10 mL) was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue dissolved in methylene chloride. The methylene chloride was removed in vacuo and the residue dissolved again in methylene chloride. The solvent was removed in vacuo and the residue used without purification. MS: Calc'd for C11H16N2O2S: 240.09. Found (M+1): 241.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]3[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[C:18]([F:26])[CH:17]=3)[CH:9]=2)=[C:4]([CH3:27])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]3[CH:25]=[CH:24][C:19]([CH2:20][OH:21])=[C:18]([F:26])[CH:17]=3)[CH:9]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: COC(=O)c1ccc(OCc2cccc(-c3ccc(Cl)cc3C)c2)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1cccc(COc2ccc(CO)c(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, a THF solution of methyl 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]-2-fluorobenzoate was dropwise added to a THF suspension of lithium aluminum hydride under cooling on an ice-methanol bath, followed by stirring at room temperature for 1 hour to obtain 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]-2-fluorobenzyl alcohol. By adding manganese dioxide to a THF solution of the resulting 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]-2-fluorobenzyl alcohol and stirring at 40° C. for 17 hours, 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]-2-fluorobenzaldehyde was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])(=O)C.[K+].CN(C=O)C>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.O>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:23]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cccnc3F)ccc1OCC2
Temperature: 105 °C
Yield: 80.3 %

Procedure:
10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 (0.057 g, 0.15 mmol), 2-fluoropyridin-3-ylboronic acid (0.026 g, 0.183 mmol), potassium acetate (0.059 g, 0.609 mmol), and tetrakis(triphenylphosphine)palladium(0) (8.8 mg, 0.007 mmol), DMF (6 mL) and water (0.6 mL) were mixed. Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was allowed to stir and heat at 105° C. for 24 hours before cooling, diluting with EtOAc, and filtering through a pad of celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (47 mg, 80%). MS (ESI(+)): m/z 391.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][C:29](Cl)=[O:30]>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:29](=[O:30])[CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:11]1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccs1)Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing 2-thiopheneacetyl chloride (50 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 48.6 mg of the product: MS m/z 459 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N:19](CC1C=CC=CC=1)CC1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:19][C:3]1[CH:4]=[C:5]([C:8]2([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(Cl)c(N(Cc3ccccc3)Cc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1(c2ccc(Cl)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
135 mg (0.29 mmol) of tert-butyl {1-[4-chloro-3-(dibenzylamino)phenyl]cyclopropyl}acetate were dissolved in 10 ml of ethyl acetate, 15 mg of palladium on carbon (10%) were added and the mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure for 2 h. The reaction mixture was then filtered off through celite, the residue was washed with ethyl acetate and the filtrate was concentrated. This gave 73 mg of the title compound (89% of theory).