Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[Na].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N>[CH2:13]([N:6]1[CH:7]=[N:8][C:4]([CH2:3][C@@H:2]([C:9]([OH:11])=[O:10])[NH2:1])=[CH:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: N
Agent: [Na]
Product: N[C@@H](Cc1cn(Cc2ccccc2)cn1)C(=O)O

Procedure:
The product 1 was synthesized by treating a solution of L-histidine (80 g, 138 mmol) in liquid ammonia (600 mL) at -70° C. with sodium (36 g) and benzylchloride (48 mL, 416 mmol). The desired product crystallized from a water solution at pH 8 and, after recrystallization from ethanol/water, 7/3, was obtained in a 56% (52.2 g) yield: mp 234-238° C. (lit. mp 248-249° C. corr).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[N:5]=[C:4]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Si:34]([O:41][CH2:42][CH2:43][C:44]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>C1COCC1>[Si:34]([O:41][CH2:42][CH2:43][C:44]1([S:47]([N:12]2[C:4]3=[N:5][CH:6]4[N:10]([CH3:11])[CH:9]=[N:8][CH:7]4[C:2]([Cl:1])=[C:3]3[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:13]2=[O:23])(=[O:48])=[O:49])[CH2:46][CH2:45]1)([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35]
Reactant: Cn1cnc2c(Cl)c3c(nc21)[nH]c(=O)n3-c1ccc(I)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCC1(S(=O)(=O)Cl)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C=NC2C(Cl)=c3c(n(S(=O)(=O)C4(CCO[Si](C)(C)C(C)(C)C)CC4)c(=O)n3-c3ccc(I)cc3F)=NC21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-chloro-1-(2-fluoro-4-iodophenyl)-5-methyl-3,5-dihydrodiimidazo[4,5-b:4′,5′-e]pyridin-2(1H)-one (example 16, step B) (150 mg, 0.35 mmol) in THF (5 ml) at −78° C. is added LiHMDS (0.39 ml, 1 M in THF, 0.39 mmol). The reaction mixture is stirred at −78° C. for 30 min and 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropane-1-sulfonyl chloride (144 mg, 0.48 mmol) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction is quenched with saturated aqueous NH4Cl solution (20 ml) and extracted with EtOAc (2×30 ml). The combined organic solution is washed with brine (30 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the desired product.
Reaction SMILES: C[O:2][C:3](=[O:37])/[C:4](=[N:16]\[O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[C:5]1[N:9]=[C:8]([NH:10]C(OCC)=O)[S:7][N:6]=1.[OH-].[Na+].C(O)C.Cl>>[NH2:10][C:8]1[S:7][N:6]=[C:5](/[C:4](=[N:16]/[O:17][C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)/[C:3]([OH:37])=[O:2])[N:9]=1
Reactant: CCOC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC)ns1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)ns1
Temperature: 5 °C
Yield: 89.7 %

Procedure:
Into a 500 mL round bottom flask equipped with mechanical stirrer, reflux condenser and nitrogen purge was charged (Z)-methyl-2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)-triphenylmethyloxyiminoacetate (20.0 g, 0.04 mol, 1.0 eq) followed by 200 mL of a 2:1 solution of 2.5 M NaOH/ethanol. The resulting biphasic solution was heated to reflux and maintained there for 15 hours. The solution was cooled to 5° C. and the pH was slowly adjusted to 3-3.5 with concentrated HCl. The precipitated white solid was filtered and washed with cold water (3×100 mL). Removal of water by coevaporation with toluene (3×200 mL), followed by drying under high vacuum at 40° C. gave 15.44 grams of the title compound as a white fluffy solid. 1H NMR (DMSO) δ 7.20-7.45. Mass spectral analysis confirms product identity.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:17]([CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]#[N:22])[C:16](=[O:27])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:28])[CH:14]=3)[N:9]=2)[CH2:3]1.[OH-:29].[Na+].OO.Cl>C1COCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:17]([CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]([NH2:22])=[O:29])[C:16](=[O:27])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:28])[CH:14]=3)[N:9]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCCC(N)C2)nc2ccc(F)cc2c1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1Cn1c(N2CCC[C@@H](N)C2)nc2ccc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[2-(3-amino-piperidin-1-yl)-6-fluoro-4-oxo-4H-quinazolin-3-ylmethyl]-benzonitrile (Example 6,50 mg) in 5 mL of THF was added 2 mL of 1N NaOH, followed by 2 mL H2O2. After stirring at room temperature overnight, the mixture was acidified with concentrated HCl. Removal of the solvent and purification by Preparative LC/MS provided the title compound. 1H NMR (400 MHz, MeOD): δ 7.68-7.74 (m, 1H), 7.59-7.66 (m, 1H), 7.48-7.58 (m, 2H), 7.29-7.40 (m, 2H), 7.02 (d, J=6.57 Hz, 1H), 5.58 (AB q, J=22.74, 15.66 Hz, 2H), 3.49-3.59 (m, 2H), 3.17-3.26 (m, 1H), 3.01-3.10 (m, 2H), 1.64-2.09 (m, 4H). MS: (ES) [m+H] calculated for C21H22FN5O2, 396; found 396.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:16][CH:17]([CH3:19])[CH3:18]>CC#N>[CH2:16]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH:17]([CH3:19])[CH3:18]
Reactant: Oc1ccccc1O
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)COc1ccccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A 50 mL round-bottom flask was charged with catechol (499 mg, 4.53 mmol), CH3CN (4.5 mL), and Cs2CO3 (1.50 g, 4.60 mmol) and purged with nitrogen. This white suspension was allowed to stir for 10 minutes prior to the addition of 1-iodo-2-methylpropane (1.67 g, 9.06 mmol). The reaction was brought to reflux and allowed to stir for 18 h. After cooling to room temperature the solvent was concentrated in vacuo, and the residue partitioned between ethyl acetate (50 mL) and 1 N HCl (50 mL). The organic layer was separated, dried, filtered, and concentrated in vacuo. Flash chromatography (3:1 hexane:ethyl acetate) afforded a yellow oil weighing 316 mg (30% yield). 1H NMR (CDCl3): δ 1.05 (dd, J=1.95 Hz, J=6.85 Hz, 6H), 2.13 (s-7, J=6.60 Hz), 3.81 (d, J=6.60 Hz), 6.81-6.88 (m, 3H), 6.93-6.95 (m, 1H); 13C NMR (CDCl3): δ 19.39, 28.38, 75.31, 111.77, 114.57, 120.22, 121.12, 121.44, 146.16.
Reaction SMILES: Cl.[CH:2]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:13])=[C:6]([CH3:38])[CH:5]=1)=O.C(O)(=O)C.[NH2:43][CH2:44][C@@H:45]([C:54]1[CH:55]=[CH:56][C:57]([OH:63])=[C:58]([NH:60][CH:61]=[O:62])[CH:59]=1)[O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CO>[Si:47]([O:46][C@H:45]([C:54]1[CH:55]=[CH:56][C:57]([OH:63])=[C:58]([NH:60][CH:61]=[O:62])[CH:59]=1)[CH2:44][NH:43][CH2:2][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:13])=[C:6]([CH3:38])[CH:5]=1)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a 2 L three-necked round-bottom flask was added biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester hydrochloride (38 g, 70 mmol) and N-{5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-hydroxyphenyl}formamide acetic acid salt (33.6 g, 91 mmol). Dichloromethane (500 mL) and methanol (500 mL) were added and the resulting mixture was stirred at room temperature under dry nitrogen for about 3 hours. The reaction mixture was then cooled to 0° C. to 5° C. and solid sodium triacetoxyborohydride (44.5 g, 381 mmol) was added in portions over a 10 minute period. The reaction mixture was slowly warmed from 0° C. to room temperature over a period of about 2 hours and then cooled to 0° C. Saturated aqueous sodium bicarbonate (500 mL) and dichloromethane (500 mL) were added. This mixture was stirred thoroughly and then the layers were separated. The organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)-ethyl]piperidin-4-yl ester (55 g, 86% purity) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[C:6]([I:8])[CH:7]=1.N([O-])=O.[Na+].S(=O)(=O)(O)N.[N-:26]=[N+:27]=[N-].[Na+]>CO.Cl.O.C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:5]=[C:6]([I:8])[CH:7]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1cc(N)cc(I)c1
Agent: Cl
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(I)cc(N=[N+]=[N-])c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 86.3 %

Procedure:
A stirred solution of 3-amino-5-iodophenylcarbamic acid, 1,1-dimethylethyl ester (A-2, 4.32 g, 13.0 mmol) in methanol (115 mL) and 1 N aqueous HCl (115 mL) is cooled to 0° C., add 1.2 M aqueous NaNO2 (12.9 mL). The reaction mixture is stirred at 0° C. for 25 min, then sulfamic acid (1.26 g, 13.0 mmol) is added followed by sodium azide (1.01 g, 15.6 mmol) in water (6 mL). Stirring is continued at 0° C. for thirty minutes and then the reaction mixture is poured into chloroform (400 mL). The phases are separated and the aqueous phase is extracted with chloroform (2×150 mL). The combined organics are dried (MgSO4), filtered and concentrated. The organic residue is purified by flash chromatography using 20% ethyl acetate in hexane as the eluent to afford 4.04 g of 3-azido-5-iodophenylcarbamic acid, 1,1 -dimethylethyl ester (A-3) as an orange colored oil. This material is used immediately in the next reaction, Step A-4. IR (liquid)3308, 2981, 2119, 2105, 1709, 1691, 1599, 1580, 1537, 1528, 1456, 1451, 1414, 1367, 1276, 1257, 1244, 1160 cm-1 ; 1H NMR (CDCl3) δ7.47 (s, 1 H), 7.09 (t, 1 H, J=2 Hz), 7.01 (t, 3 H, J=2 Hz), 6.00 (bs, 1 H), 1.51 (s, 9 H); 13C NMR (CDCl3) δ152.0, 141.5, 140.4, 123.2, 122.0, 108.1, 94.2, 81.2, 28.0; Mass Spec (70eV, EI) m/z 360 (parent), 304, 276, 248, 232, 205, 149, 131, 105, 77, 57 (base), 40. Exact mass calculated for C11H13IN4O2 : 360.0085. Found: 360.0051.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[C@H:12]([C:13]([CH2:15]O)=[CH2:14])[CH2:11][N:10]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>ClCCl>[C:1]([O:5][C:6]([C@H:8]1[C@H:12]([C:13]([CH2:15][Br:47])=[CH2:14])[CH2:11][N:10]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(CO)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(CBr)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
(3S,4R)-1-Benzyloxycarbonyl-4-[1-(hydroxymethyl)vinyl]pyrrolidine-3-carboxylic acid tert-butyl ester (30.0 g, 83.0 mmol) was dissolved in dichloromethane (300 mL). Triphenylphosphine (23.2 g, 87.2 mmol) and carbon tetrabromide (29.4 g, 87.2 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→1:1) to give 26.9 g of the title compound as a colorless oil.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]2[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]2)=[N:18]1.O>CS(C)=O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]2[CH2:31][CH2:30][N:29]([C:2]#[N:1])[CH2:28][CH2:27]2)=[N:18]1
Reactant: CN1CCC(c2nn(-c3ccccc3F)c3ccccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCC(c2nn(-c3ccccc3F)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 31 %

Procedure:
To a stirred mixture of cyanogen bromide (15.5 g, 0.146 moles) and potassium carbonate (23.7 g, 0.167 moles) in dimethylsulfoxide (DMSO) [300 ml] was added dropwise a solution of 1-(2-fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole, the free base of example 36, (42.0 g, 0.137 moles) in dimethylsulfoxide (40 ml). The reaction temperature rose to 36° C. and the mixture was stirred at ambient temperature for 2.5 days. The reaction mixture was then poured into H2O and the product extracted with ether. The ether was dried (MgSO4) and concentrated which left 40 g of a solid. The product was recrystallized 5 times from isopropyl alcohol which yielded 13.6 g (31%) of 4-[1-(2-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, m.p. 119°-121° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.CCN(CC)CC>C(Cl)Cl>[C:26]1([C:13]2([CH:12]=[O:11])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]3[C:25]2=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCC1(c2ccccc2)c2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC1(c2ccccc2)c2ccccc2-c2ccccc21
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (5.07 mmol) in CH2Cl2 (10 mL) at -60° C. is added DMSO (10.56 mmol) in CH2Cl2, dropwise under an argon atmosphere. The resulting mixture is stirred at -60° C. for 5 min, and a solution of 9-hydroxymethyl-9-phenylfluorene (4.4 mmol) in CH2Cl2 (2 mL) is then added dropwise over 10 minutes to the reaction mixture. The reaction mixture is allowed to stir at -50° C. for another 15 min after the addition is completed. Et3N (3 mL) is added dropwise and the resulting mixture allowed to warm to room temperature over 30 min. The reaction mixture is quenched with H2O (15 mL). The resulting mixture is extracted with CH2Cl2 (2×30 mL). The combined CH2Cl2 layers are washed with brine (1×30 mL), dried (Na2SO4) and concentrated in vacuo to afford the crude aldehyde.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]([C:8]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[Cl:24])[O:16][N:15]=2)[CH:11]=[CH:10][C:9]=1[Cl:25])[CH3:7])C.[OH-].[Na+].Cl>C1COCC1.C(O)C.O>[Cl:25][C:9]1[CH:10]=[CH:11][C:12]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][C:23]=3[Cl:24])[O:16][N:15]=2)=[CH:13][C:8]=1[N:6]([CH2:5][C:4]([OH:26])=[O:3])[CH3:7]
Reactant: CCOC(=O)CN(C)c1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(=O)O)c1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reaction time: 48 h
Yield: 42 %

Procedure:
To a white suspension of ({2-chloro-5-[5-(3-chlorothiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methylamino)-acetic acid ethyl ester (0.362 g, 0.880 mmol) in an EtOH:H2O solution (4:1, 13.4 mL) was added 1M NaOH (0.033 mL, 0.84 mmol). Additional aliquots of 1M NaOH (1.98 μL, 50.34 mmol), ethanol (8 mL) and THF (10 mL) was added and the mixture was stirred for 2 days until the reaction was complete by TLC. The reaction suspension was neutralized by the addition of 1M HCl and concentrated to a white solid. The white solid was filtered and washed with H2O and ether to yield 0.142 g (44%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): 8.19 (dd, 1H, J=5.2 and 0.8 Hz), 7.79 (s, 1H), 7.52 (dd, 2H, J=8.2 and 6.3 Hz), 7.41 (dd, 1H, J=5.5 Hz), 3.77 (s, 2H), 2.97 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][S:10](=[O:18])[C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][S:10](=[O:18])[C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]2=3)=[CH:27][CH:26]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: O=S1Cc2ccccc2N(C[C@@H]2CCCN2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CS(=O)c3ccccc32)cc1
Yield: 19.4 %

Procedure:
A mixture of (2S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine-10-oxide (see Preparation 19) (180 mg), 4-methoxyphenethyl bromide (140 mg) and sodium carbonate (70 mg) in acetonitrile (20 ml) was heated under reflux for 18 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (5 g), performing a gradient elution initially using dichloromethane as eluant and changing to dichloromethane/methanol (98:2). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (50 mg, 19%).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl[C:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:11]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH:35]2[CH2:37][C@H:32]1[CH2:33][NH:34]2)=[O:30])([CH3:27])([CH3:26])[CH3:25].O>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH:35]2[CH2:37][C@H:32]1[CH2:33][N:34]2[C:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:11]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CC(C)(C)OC(=O)N1CC2C[C@H]1CN2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(N2C[C@@H]3CC2CN3C(=O)OC(C)(C)C)nc(-c2ccncc2)cc1=O
Temperature: 20 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
A mixture containing 10.7 ml (78.14 mmol) of triethylamine, 13.6 g (52.7 mmol) of 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one hydrochloride (1:1), 6.0 g (30.24 mmol) of (1S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in 500 ml of anhydrous dimethylformamide is stirred at 20° C. for 6 h. Water is added to the cooled mixture and the resulting solution extracted with ethyl acetate. The combined extracts are washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride then-evaporated. The crude product is refluxed in diethylether for 1 h to afford 8.36 g of pure product as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:15][C:14]=1[F:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:10])[C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:15][C:14]=1[F:26]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(O)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC(=O)OC(C)C)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2,5-dimethyl-phenol (220 mg, 0.62 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (301 mg, 0.92 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (134 mg, 0.74 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 h. TLC showed the starting material was not consumed. A further portion of Cs2CO3 (300 mg, 0.92 mmol, 1.5 eq) was added and the reaction stirred for 1 h, then a further portion of isopropyl bromoacetate (134 mg, 0.74 mmol, 1.2 eq) was added and the reaction stirred for 4 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 20:1) to give the title compound as a colorless oil (225 mg, 80%).
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[C:5]([C:9]([C:12]([O:15][C:16]([C:22](F)=[O:23])([C:18]([F:21])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])([F:7])[F:6]>ClC1C=CC=CC=1Cl>[C:5]([C:9]([C:12]([O:15][C:16]([C:22]([Cl:2])=[O:23])([C:18]([F:21])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])([F:7])[F:6]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1Cl
Product: O=C(Cl)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 60 °C

Procedure:
A mixture of AlCl3 and o-dichlorobenzene (4 mL) was treated with CF3CF2CF2OCF(CF3)COF (13.2 g, 40 mmol) and heated at 60° C. for 0.5 hr. Volatiles were removed by vacuum transfer (27 Pa) to give a mixture of two liquids. The lower layer was separated and distilled to provide 8.0 g of colorless liquid, bp ca. 65° C. GC analysis showed 99% purity. 19F NMR (F11): -81.32 (s, CF3), -81.94 (t, J=7.3 Hz, CF3), -79.05 and -84.98 (AB pattern, J=146 Hz, OCF2), -126.1 (d of m's, J=23, CF), -130.1 (s, CF2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[C:11](C)(C)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(OC)cc1

Procedure:
To a solution of 4-methoxyphenol (500 mg, 4.03 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (807 mg, 4.84 mmol) and K2CO3 (3 g, 21.7 mmol) at 25° C. The mixture was refluxed for 16 h. The mixture was then diluted with water (100 mL), extracted with ethyl acetate (2×50 mL) and the combined organic layers washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.