Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:40])C.[OH-].[Na+].Cl>C(O)C>[CH3:40][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(Oc3ccc(C(F)(F)F)cn3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (262 mg; 0.45 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 174 mg (68%). HPLC-MS: m/z: 559.5 (M+H)+; Rt: 1.81 min.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1)=[C:2]=[S:3].[N-:15]=[N+:16]=[N-:17].[Na+].Cl>O>[C:8]([C:7]1[CH:13]=[CH:14][C:4]([N:1]2[C:2]([SH:3])=[N:17][N:16]=[N:15]2)=[CH:5][CH:6]=1)([OH:10])=[O:9]
Reactant: CCOC(=O)c1ccc(N=C=S)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(-n2nnnc2S)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.3 %

Procedure:
Then, 31 g of ethyl p-isothiocyanatobenzoate and 11.7 g of sodium azide were dispersed in 300 ml of water and the dispersion was refluxed for 5 hours. The reaction mixture was cooled to room temperature and acidified (pH about 2) by the addition of concentrated hydrochloric acid. Crystals of 1-(4-ethoxycarbonylphenyl)-5-mercaptotetrazole thus deposited were collected by filtration and after adding thereto 25 g of sodium hydroxide and 500 ml of water, the mixture was stirred for 30 minutes at 70° C. The reaction mixture was cooled to room temperature, neutralized by the addition of concentrated hydrochloric acid, and crystals thus deposited were collected by filtration and recrystallized from methanol to provide 40 g of 1-(4-carboxyphenyl)-5-mercaptotetrazole. The yield was 48% and the melting point was 198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26]([NH:28]CC)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26]([NH2:28])=[O:27])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCNC(=O)[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C(N)=O)c1nnc(C)n1-2

Procedure:
A procedure analogous to that used for Compound 204 was followed, with the exception that ammonium chloride was used instead of ethylamine hydrochloride. LRMS (M+H)+: 412 m/z. 1H NMR (major conformer reported only) (400 MHz, DMSO-d6) δ 7.38-7.54 (m, 4H), 6.83 (br. s., 1H), 6.69 (br. s., 1H), 2.62 (s, 3H), 2.35 (s, 3H), 2.06 (dd, J=5.04, 8.93 Hz, 1H), 1.93 (t, J=6.20 Hz, 1H), 1.81 (t, J=7.80 Hz, 1H), 1.48 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]I)[N:6]=1.[C-:9]#[N:10].[Na+]>CS(C)=O.C(OCC)C.O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:9]#[N:10])[N:6]=1
Reactant: Brc1nc(CI)cs1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: N#CCc1csc(Br)n1
Reaction time: 0.67 h
Yield: 85.1 %

Procedure:
A solution of 2-bromo-4-(iodomethyl)thiazole (2.11 g, 6.942 mmol) in DMSO (15 mL) under nitrogen was treated with sodium cyanide (345.0 mg, 7.039 mmol) and allowed to stir for 40 minutes. The reaction was diluted with diethyl ether/water and the layers separated, the aqueous was extracted further with ether (2×) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated. The resultant residue was purified by column chromatography (3:1 Petroleum ether/EtOAc) to afford the product as a white solid (1.20 g, 86% Yield). 1H NMR (CDCl3, 400 MHz) δ 3.91 (2H, s), 7.31 (1H, s); MS (ES+) 204.95
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]1[CH2:12][CH:11]2[NH:13][CH:7]([CH2:8][O:9][CH2:10]2)[CH2:6]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:13]1[CH:7]2[CH2:6][CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH2:12][CH:11]1[CH2:10][O:9][CH2:8]2)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)CC1CC2COCC(C1)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (Compound AG) (179 mg, 0.90 mmol) in 10 mL of dichloromethane was added triethylamine (0.5 mL, 3.6 mmol). The mixture was stirred at room temperature for 15 mins and then benzyl chloroformate (0.25 mL, 1.8 mmol) was added dropwise at 0° C. After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated in vacuo. The residue was purified by flash column chromatography to afford 7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester as colorless oil (Compound AI) (0.13 g, 44%) MS: calc'd (MH+) 334, measured (MH+) 334.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:13][C:14]2([NH:17]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[C:25]([NH:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:26].Cl.N>CO.O1CCOCC1>[NH2:17][C:14]1([CH2:13][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:25]([NH:27][CH2:28][C:29]23[CH2:30][CH:31]4[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]4)[CH2:36]2)[CH2:38]3)=[O:26])[CH2:10][CH2:11][OH:12])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
[1-[[[[4-Chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-methyl](2-hydroxyethyl)amino]methyl]cyclopropyl]-carbamic acid, 1,1-dimethylethyl ester (Example 71d, 0.302 g) was dissolved in methanol (10 ml) and 4 N HCl in dioxane (10 ml) was added. The mixture was stirred for 14 h at room temperature, then poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica (eluting with 19:1:0.1 dichloromethane/methanol/ammonia) to afford the title compound as an oil (0.230 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17].OO.NC(N)=O.P([O-])([O-])(O)=O.[K+].[K+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:6]([O-:17])[CH:7]=1
Reactant: CCOC(=O)c1ncc(Br)cc1F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: O=P([O-])([O-])O
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)c1c(F)cc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 5-bromo-3-fluoro-pyridine-2-carboxylate (2, 0.9 g, 3.63 mmol) in dichloromethane (50 mL) at 0° C. was added trifluoroacetic anhydride (1.52 g, 7.26 mmol), urea hydrogen peroxide (0.72 g, 7.62 mmol). The reaction mixture was stirred at room temperature overnight. After the oxidation was complete the reaction mixture was neutralized with a dipotassium hydrogenphosphate solution and quenched with a sodium bisulfite solution. The product was extracted with dichloromethane (2×100 mL). The organic layers were separated, dried with magnesium sulfate, filtered and concentrated to dryness under vacuum to afford ethyl 5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate (3) as an off-white solid. Yield: 0.9 g, 89%; MS (ESI) m/z 265.95 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ: 8.22 (s, 1H), 7.30-7.26 (m, 1H), 4.50 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@H:11]4[C@:18]([CH3:27])([CH2:19][C:20](=[O:26])[C:21]=32)[C@@H:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:12]4)[CH2:6]1)(=O)C.Cl(O)(=O)(=O)=O.O>CO>[OH:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@H:11]4[C@:18]([CH3:27])([CH2:19][C:20](=[O:26])[C:21]=32)[C@@H:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:12]4)[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC[C@]2(C)C3=C(CC[C@H]2C1)[C@@H]1CC[C@H](C(C)=O)[C@@]1(C)CC3=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2C3=C(C(=O)C[C@]12C)[C@@]1(C)CC[C@@H](O)C[C@@H]1CC3
Reaction time: 19 h
Yield: 38 %

Procedure:
3α-Acetoxy-5α-pregn-8-ene-11,20-dione (400 mg.) was dissolved in methanol (40 ml.) and perchloric acid (60% w/v; 2 ml.) was added and the solution was allowed to stand at room temperature for 19 hours. The reaction mixture was poured into water and the steroid extracted with chloroform. The solvent was removed from the extract and the residue twice crystallised from methyl acetate-petrol to give the title compound (135 mg.) m.p. 170°-172°, [α]D + 250°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20](Cl)[O:21][CH3:22].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH:9]1[C:10]([N:20]([O:21][CH3:22])[CH3:19])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: CON(C)Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON(C)C(=O)C1CC(C)(C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 83.9 %

Procedure:
To a stirred solution of 1-tert-butyloxycarbonyl-4,4-dimethylpipecolic acid (24.6 g), N,O-dimethylhydroxylamino hydrochloride (12.12 g) and 1-hydroxybenzotriazole (18.09 g) in anhydrous dimethylformamide (400 ml) was added anhydrous triethylamine (30.7 ml) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.08 g) and the resulting mixture was stirred at room temperature for 23 hours under a nitrogen atmosphere. Diethyl ether (1 l) was added and the mixture was washed with 1N hydrochloric acid (2×250 ml), 1N sodium hydroxide (1×250 ml), brine (1×200 ml), dried (MgSO4) and concentrated. Flash chromatography (silica gel, hexane-diethyl ether, 40:60) of the residue afforded the title compound (24.1 g) as a white solid; δH (250 MHz, CDCl3) 4.76 (1H, br s), 3.92-3.74 (1H, m), 3.75 (3H, s), 3.58-3.42 (1H, m), 3.19 (3H, s), 1.84 (1H, dd, J=14.0 and 3.3 Hz), 1.64 (1H, dd, J=14.0 and 7.6 Hz), 1.52-1.34 (11H, m and s), 0.94 (3H, s), 0.92 (3H, s); m/z (CI)301 (M+ +1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccccc1
Product: O=C(CCCl)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Trifluoromethylaniline (0.3 mole), β-chloropropionyl chloride (0.35 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(4-trifluoromethylphenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1CC[CH2:17][CH2:16][CH2:15]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:13][CH2:17][CH2:16][CH2:15][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: C1CCNCC1
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Product: NC(=O)c1cc(N2CCCCC2)ccc1N

Procedure:
According to the preparation of 25, piperidine was used to afford 27 (0.8 g) as brown powder; MS m/z 219 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH3:31].Cl[CH2:33][C:34](=[O:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:34]([CH2:35][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[C:25]5[CH3:31])=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:16][CH2:17]1)(=[O:36])[CH3:33]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCNCC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(CC(C)=O)CC1
Temperature: 70 °C

Procedure:
A mixture of 6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quinazoline (0.2 g), chloroacetone (0.046 ml), potassium carbonate (0.1 g) and DMF (6 ml) was stirred and heated to 70° C. for 1 hour. The mixture was cooled to ambient temperature, the precipitate was removed by filtration, the solvent was removed by evaporation under vacuum and the residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with dichloromethane and ending dichloromethane/methanol (93/7). Evaporation of the solvents gave a foam which was triturated under ether/pentane (70/30) to give a solid which was collected by filtration and dried under vacuum to give 7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (0.074 g).
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].ClC(Cl)(Cl)C(O)=[O:12].O>C(Cl)Cl>[Cl:1][C:2]([Cl:8])=[CH:3][CH:4]1[O:12][C:5]1([CH3:7])[CH3:6]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC1C=C(Cl)Cl
Reaction time: 15 h
Yield: 101.8 %

Procedure:
To 30.6 g (0.2 mole) of 1,1-dichloro-4-methyl-1,3-pentadiene in 400 ml methylene chloride were added 0.35 mole of technical perchloroacetic acid containing 1.0 g sodium acetate at a temperature of 10°-20° C. over a period of 20 minutes. After stirring for 15 hours, the reaction mixture was poured into 500 ml of water. The phases were separated and the aqueous phase extracted twice with 150 ml of methylene chloride. The organic phases were combined and washed with 10% aqueous sodium carbonate (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over Na2SO4 and the solvent evaporated. The product was distilled to give 34 g of 1,1-dichloro-3,4-epoxy-4-methyl-1-pentene (82% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:16][C:15]=4[CH3:30])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:34][O-:35].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[N:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][C:11]3[C:12]([O:35][CH3:34])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:16][C:15]=4[CH3:30])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C[O-]
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3-(4-(1H-pyrazol-1-yl)benzyl)-2,4-dichloro-8-methylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1.05 g, 2.20 mmol, Intermediate 14: step a) and dry sodium methoxide (0.59 g, 11.02 mmol) in toluene (10 mL) was heated in a sealed tube at 110° C. for 12 hours. The mixture was cooled to room temperature, diluted with DCM, stirred for 30 minutes at room temperature and the resulting suspension filtered through Celite®, rinsing several times with DCM. The solvents were removed under reduced pressure and the residue chromatographed (DCM/10% MeOH in DCM, gradient) to provide the crude product. Recrystallization from MeOH, filtering and drying under reduced pressure overnight provided the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].C([O-])(O)=O.[Na+].[C:14](ON1C(=O)CCC1=O)([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15].CCOCC.O>O.CC(C)=O>[C:14]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5])([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15]
Reactant: N[C@@H](CCO)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: O=C(N[C@@H](CCO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 88 %

Procedure:
L-homoserine (15 g, MW119.12, 0.126 mol) and NaHCO3 (22 g, MW84, 0.26 mol) were dissolved in water (600 mL). The solution was chilled in an ice bath, followed by addition of Fmoc-OSu (42.5 g, MW337.3, 0.126 mol) in acetone (400 mL). The mixture was stirred overnight. A mixture of ether/water (200 mL/200 mL) was added, and the solid was filtered off. The filtrate was separated and the aqueous phase was washed with ethyl twice (100 mL×2), followed by acidifying with 3N HClaq (about 100 mL) to pH3-4. The suspension was extracted with ether (200 mL×2). The combined organic phases were washed with brine once (100 mL) and dried over Na2SO4. After evaporation, white solid was obtained (weight: 38 g, yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([Br:18])=[CH:16][C:15]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][C:13]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[CH:6][C:5]=1[O:46]C.[K+].[Br-]>>[CH3:1][O:2][C:3](=[O:48])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([Br:18])=[CH:16][C:15]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:14][C:13]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[CH:6][C:5]=1[OH:46]
Reactant: COC(=O)c1ccc(COc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1OC
Agent: [Br-]
Agent: [K+]
Product: COC(=O)c1ccc(COc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O

Procedure:
The title compound was prepared as a light yellow oil (0.361 g, 37%) from 4-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3′-trifluoromethyl-biphenyl-2-yloxymethyl]-2-methoxy-benzoic acid methyl ester using a procedure similar to Example 200. 1H NMR (DMSO-d6) δ10.45 (s, 1H); 8.59 (bt, 1H); 8.18 (d, 1H); 7.90-7.58 (m, 6H); 7.25-7.10 (m, 5H); 6.70-6.60 (m, 2H); 4.60 (s, 2H); 3.88 (s, 3H); 3.24 (dd, 2H); 2.52 (t, 2H); 1.50 (m, 4H); 1.25 (m, 8H); IR (KBr) 3400, 2950, 2850, 1685, 1620, 1550, 1440, 1400, 1180, 1120 cm−1; mass spectrum [(−)APCI], m/z 710 (M−H)−; Anal. Calcd. for C37H37BrF3NO5: C, 61.90; H, 5.05; N, 2.01, Found: C, 60.59; H, 5.09; N, 1.86.
Reaction SMILES: CN(C)CCN[C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].[NH2:44][CH2:45][CH:46]([OH:49])[CH2:47][OH:48]>>[OH:49][CH:46]([CH2:47][OH:48])[CH2:45][NH:44][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7]
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: NCC(O)CO
Product: O=C(N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)NCC(O)CO)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to racemic 3-amino-1,2-propanediol under standard TBTU conditions to yield the title compound of example 140.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)(=O)C.[Ni]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:12]=[N:13][N:14]=[CH:15]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(-n2cnnc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(=O)O
Product: Cc1cc(-n2cnnc2)ccc1N

Procedure:
A solution of 4-(3-methyl-4-nitrophenyl)-1,2,4-triazole (1.0 g) in acetic acid (25 cm3) was hydrogenated at 25° and 60 p.s.i. (4.13×105Pa) pressure over Raney nickel (0.2 g) for 2 hours. The mixture was then filtered through "Solkafloc" (Trade Mark for a cellulose based filtering agent), the solvent was evaporated in vacuo and the residue was partitioned between chloroform (100 cm3) and aqueous sodium carbonate solution (20 cm3). The aqueous phase was further extracted with chloroform (3×50 cm3) and the combined and dried (MgSO4) organic extracts were concentrated to afford an oil which waschromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:ethyl acetate, 1:9. Combination and evaporation of the appropriate fractions afforded a solid which was recrystallised from ethyl acetate/hexane to give 4-(4-amino-3-methylphenyl)-1,2,4-triazole, m.p. 152°-154° (0.67 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.CN1CCOCC1.[CH2:25]([N:27]([CH2:43][CH3:44])[C:28]1[C:33]([CH:34]=[CH:35][C:36](O)=[O:37])=[CH:32][CH:31]=[C:30]([C:39]([F:42])([F:41])[F:40])[N:29]=1)[CH3:26].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[CH2:43]([N:27]([CH2:25][CH3:26])[C:28]1[C:33]([CH:34]=[CH:35][C:36]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:37])=[CH:32][CH:31]=[C:30]([C:39]([F:42])([F:40])[F:41])[N:29]=1)[CH3:44]
Reactant: CCN(CC)c1nc(C(F)(F)F)ccc1C=CC(=O)O
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N(CC)CC)cc(F)c1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a suspension of N-(4-aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (476 mg, 1.66 mmol) in THF (5 mL) was added N-methylmorpholine (0.365 ml, 3.32 mmol). The mixture was stirred for 5 minutes, to which were added 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (434 mg, 1.51 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 459 mg, 1.66 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from CH2Cl2 to give the title compound (645 mg, 83%).