Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.O.[Cl-].[Na+]>[C:25]([NH:29][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
To a cooled to −30° C. solution of indole-5-carboxylic acid and triethylamine in DMF was added methyl sulfonyl chloride in portions to avoid temperature elevation. Following the addition, solution was warmed to room temperature and was stirred for 1 hour and 15 minutes. Reaction mixture was then cooled to −20° C. and N-tert-butyl-amine was added in two portions so the temperature remained at −10° C. After 13 hours of stirring, the solution was diluted with water and saturated with sodium chloride. The solution was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound as a thick brown oil (NMR showed 34% DMF) (28% yield), melting point=176.4° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C=C[CH:48]=[C:47]([Cl:51])[CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:44]=[CH:45][CH:46]=[C:47]([Cl:51])[CH:48]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CBr)c1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(Cl)c3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-3-chlorobenzene and isolated as light-yellow gum (7.0 mg, 42%). MS(m/e): 407.4 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:15]=2[CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:27][CH3:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+]>>[CH2:32]([O:31][C:29]([N:26]([CH2:25][C:15]1[CH:16]=[C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=1)[CH2:27][CH3:28])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NS(C)(=O)=O)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Product: CCN(Cc1cc(NS(C)(=O)=O)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1

Procedure:
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-methanesulfonylamino-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.2 mmol) was hydrolyzed with lithium hydroxide to give the title compound.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=3[CH3:49])[C:44]#[N:45])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:42]=[C:43]([C:44]#[N:45])[CH:46]=[CH:47][C:48]=3[CH3:49])[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1ccc(C#N)cc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(C#N)ccc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.4 %

Procedure:
Sodium hydride (108 mg, 2.69 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (795 mg, 1.97 mmol) (Intermediate AB3) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-methylbenzonitrile (Intermediate AM2) (484 mg, 1.79 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the reaction mixture diluted with water (10 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×30 mL). The combined organics were washed with saturated brine (75 mL),dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% Et2O in isohexane to afford the product (300 mg, 26.3%). m/z (ES+) (M+H)+=636.5; HPLC tR=3.65 min.
Reaction SMILES: CN1C=CN=C1.[CH3:7][O:8][N:9]=[CH:10][CH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)O.CS([Cl:25])(=O)=O.C(OCC)(=O)C>C(#N)C.O>[Cl:25][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:11][CH:10]=[N:9][O:8][CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CON=CCCC(O)c1ccccc1
Agent: Cn1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CON=CCCC(Cl)c1ccccc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
0.24 mL of N-methylimidazole was added to a solution of 0.39 g of 4-(methoxyimino)-1-phenylbutan-1-ol in 4 mL of acetonitrile. Thereafter, 0.19 mL of methanesulfonyl chloride was added to the mixture at a temperature of 0° C. to 10° C., and the thus obtained mixture was then stirred at a temperature of 5° C. or lower for 1.5 hours. Thereafter, 0.24 mL of methanesulfonyl chloride was added to the reaction mixture, ethyl acetate and water were then added thereto, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained product was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 59/41), so as to obtain 0.07 g of (4-chloro-4-phenylbutylidene)(methoxy)amine in the form of a light yellow oily product.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10](C)=[CH:9][C:8]=1[OH:14].Cl[CH2:16]Cl>>[Cl:6][C:7]1[CH:12]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=[C:9]([CH3:16])[C:8]=1[OH:14]
Reactant: ClCCl
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(Cl)c(O)c1
Product: Cc1cc(S(=O)(=O)Cl)cc(Cl)c1O
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a solution of chlorosulfonic acid (1.22 g, 10.5 mmol) dissolved in 10 mL of dichloromethane was added 2-chloro-5-methylphenol (1.0 g, 7.0 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 190 mg (11.3%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12][CH:11]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[N:20]=2)=[CH:12][CH:11]=1
Reactant: CC1CCCN1CCOc1ccc(-c2nc(CC(=O)O)co2)cc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCN1CCOc1ccc(-c2nc(CC(=O)N3CCCCC3)co2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
A solution of (2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)acetic acid i53 (0.29 g, 0.87 mmol, 1 eq), piperidine (0.18 ml, 1.75 mmol, 2 eq) and triethylamine (0.36 ml, 3.6 mmol, 3 eq) in dichloromethane (20 ml) is cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.42 g, 2.17 mmol, 2.5 eq) and 1-hydroxybenzotriazole (0.12 g, 0.87 mmol, 1 eq) are then added. The mixture is stirred 24 h at room temperature, and washed two times with a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 97/2.7/03) affords 0.15 g of 1-[(2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)acetyl]piperidine i54.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[N:6][CH:7]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: CC(C)(C)[S@](N)=O
Solvent: ClCCl
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cncc(Br)c1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To a solution of 1-(5-bromopyridin-3-yl)ethanone (1.01 g, 5.04 mmol) in DCM (20 mL) was added (R)-2-methylpropane-2-sulfinamide (0.555 g, 4.58 mmol) followed by Ti(OEt)4 (1.23 g, 4.58 mmol) dropwise and the reaction mixture was heated to 40° C. over night. After cooling, the solvent was removed under vacuum and the residue taken up in EtOAc (80 mL). This solution was vigorously stirred while a saturated solution of brine (20 mL) was slowly added. After 15 min, the mixture was filtered through a plug of Dicalite and washed with EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give the title compound (0.964 g, 69%) as a yellow oil. MS: 303.1 and 305.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])=[CH:18][CH:17]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCc1ccc(O)cc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
3-Nitrophthalic anhydride (1.93 g, 0.01 mol, 1 eq) and 2-(4-hydroxyphenyl)-ethylamine (2.06 g, 0.015 mol, 1.5 eq) were refluxed under heating in toluene (20 ml) for 3 hours. The reaction mi i t ure was cooled to room temperature, and ethyl acetate (100 ml) was added to this reaction mixture. The organic layer was washed twice with dil. aqueous hydrochloric acid solution (30 ml), further washed with saturated brine (100 ml), and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give N-[2-(4-hydroxyphenyl)ethyl]-3-nitrophthalimide (2.92 g, 92.8%) as a colorless solid. This was further purified by recrystallization from methanol to give colorless crystals (1.9 g, 60.8%).
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(C#Cc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(C#Cc2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 M aqueous HCl (10 ml) was added slowly to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-(2-oxo-4-(phenylethynyl)pyridin-1 (2H)-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (107 mg, 0.226 mmol) in 1,4-dioxane (20 mL) at room temperature. The reaction mixture was allowed to stir at room temperature overnight. After 18 hours the reaction was concentrated to low volume then redissolved in methanol (20 ml) and concentrated in vacuo to afford a light-yellow solid. Yield 71 mg, 81%. MS (APCI) m/z 389.4 (M+H), 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (none, 3H) 1.53 (s, 3H) 2.03-2.17 (m, 1H) 2.33-2.45 (m, 1H) 3.07 (s, 3H) 3.71 (td, J=11.90, 4.88 Hz, 1H) 3.96-4.14 (m, 1H) 6.35 (dd, J=6.93, 1.85 Hz, 1H) 6.56 (d, J=1.76 Hz, 1H) 7.36-7.48 (m, 3H) 7.51-7.61 (m, 2H) 7.69 (d, J=7.02 Hz, 1H) 11.05 (br. s., 1H)
Reaction SMILES: Cl[S:2]([NH:5][C:6](=[O:26])[O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:4])=[O:3].[CH2:27]([OH:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>C1COCC1>[C:20]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[O:7][C:6](=[O:26])[NH:5][S:2]([O:39][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:4])=[O:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: CCCCCCCCCCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOS(=O)(=O)NC(=O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of [1,1':3',1"-terphenyl]-2'-yl (chlorosulfonyl)carbamate (5.0 g, 12.9 mmoles) in 75 mL THF was added dropwise to a solution of n-dodecyl alcohol (2.4 g, 12.9 mmoles) and triethylamine (1.3 g, 12.9 mmoles) in 100 mL THF at ~15° C. under an atmosphere of N2. The mixture was allowed to warm to room temperature for 16 hours, then concentrated in vacuo and partitioned between H2O and EtOAc. The EtOAc layer was dried with MgSO4 and evaporated to give a white solid. Chromatography (SiO2, 10% EtOAc/hexanes) gave 2.95 g of the title compound, mp 124°-126° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[S:24]([O:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(=[O:26])=[O:25]>C1C=CC=CC=1>[C:8]1([NH:14][N:15]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][O:27][S:24]([C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:17][CH3:16])(=[O:26])=[O:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNc1ccccc1
Reactant: COc1ccccc1S(=O)(=O)OCC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: COc1ccccc1S(=O)(=O)OCC(=NNc1ccccc1)c1ccccc1

Procedure:
Into a reactor, equipped with a Dean-Stark separator, were introduced 100 ml of benzene, 1 ml of acetic anhydride, 10.8g (0.1 mol) of phenylhydrazine and 30.6 g (0.1 mol) of 3-methoxy-4-benzenesulphonyloxy-acetophenone. The reaction medium was stired and refluxed for 1 hour.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[NH:8][N:7]=1)=[O:5])[CH3:2].O1CCCC1.[Br-:19].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])[CH2:12][Br:19])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: [Br-]
Reactant: CCOC(=O)c1cc(C(C)=O)[nH]n1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)CBr)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.7 %

Procedure:
A 100ml flask was charged with 27.8 g of 5-acetylpyrazole-3-carboxylic acid ethyl ester and 40 ml of tetrahydrofuran. To this mixture, 56.4 g of phenyltrimethylammonium tribromide were added. The resulting red mixture was stirred at room temperature for 1 hour and poured into 600 ml of water. The resulting mixture was filtered and the solids were washed with more water. The solids were collected, air-dried and recrystallized from 1:1 mixture of disopropyl ether and hexanes (300ml) to afford 33.1 g of 5-(2-bromoacetyl)pyrazole-3-carboxylic acid ethyl ester as white solids, mp 174°-176° C. NMR: 1.42 (t, 3H), 4.44 (q, 2H), 4.57 (s, 2H), 7.4 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[C:4]([O:17][CH3:18])[C:3]=1[F:19].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:30](O)[CH3:31]>>[CH2:30]([O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:19])[C:4]=1[O:17][CH3:18])([CH3:16])[CH3:15])[CH3:31]
Reactant: COc1c(C(C)(C)CC(=O)C(=O)O)ccc(Cl)c1F
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(Cl)c(F)c1OC

Procedure:
5.44 g (18.84 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 117 ml of ethanol, mixed with 2.1 ml of concentrated sulfuric acid and refluxed for six hours. The reaction mixture is added to 250 ml of saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate solution and with brine. After drying and after the desiccant is filtered off and the solvent is spun in, 5.19 g (87%) of the desired compound is obtained.
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:18][C:30]1[CH:31]=[C:26]([CH2:25][C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH:27]=[CH:28][C:29]=1[OH:32]
Reactant: [IH2+]
Reactant: Oc1ccc(Cc2ncccn2)cc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(Cc2ncccn2)cc1I
Reaction time: 1 h

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (379 mg, 1.02 mmol) was added to a solution of 4-(pyrimidin-2-ylmethyl)phenol (200 mg, 1.07 mmol) in 9:1 DCM:TFA (6 mL) at 0° C. The mixture was stirred for 1 h, partitioned between EtOAc and water, the layers were separated, and the organic layer was washed with satd. sodium thiosulfate. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give 2-iodo-4-(pyrimidin-2-ylmethyl)phenol. MS (ESI) m/z: Calculated: 312.0; Observed: 313.0 (M++1).
Reaction SMILES: [C:1]([N+:4]1([O-])[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1CC(N1CCC(=C2C3=NC=CC=C3CCC3C=C(Cl)C=CC2=3)CC1)=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[C:10]2[C:16]3=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:11]2=3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[N+]1([O-])CCC(=C2c3ccc(Cl)cc3CCc3ccc(C)nc32)CC1
Agent: O=C(Cc1ccccn1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Product: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc(C)nc32)CC1

Procedure:
1-acetyl-4-(8-chloro-5,6-dihydro-2-methyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine N-oxide i.e.,; ##STR10## 1-(2-pyridylacetyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine;
Reaction SMILES: C(N(CC)CC([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)C)C.C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH:19]1[C:20]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:14][C:15]=2[CH:16]=[CH:17][C:18]=1[C:21](=[S:32])[NH2:22]
Reactant: S
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of 10-[(2RS)-1-diethylamino-2-propyl]2-phenothiazinecarbonitrile (5.66 g) and triethylamine (2.35 cc) in pyridine (113 cc) is treated with hydrogen sulphide for 1 hour and then stirred for 3 days at a temperature in the region of 20° C. The greenish solution obtained is purged with nitrogen, poured into distilled water (500 cc) and extracted with ethyl acetate (2×500 cc). The combined organic phases are washed successively with distilled water (2×200 cc) and with saturated aqueous sodium chloride solution (200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg, 4 kPa) at 40° C. The residual orange oil (9.1 g) is purified by chromatography on a column (height: 25 cm, diameter: 3 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with ethyl acetate (750 cc) and collecting 50-cc fractions. The combined fractions 4 to 10 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (6.2 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: CO[C:3]1[CH2:4][CH:5]([CH3:11])[CH:6]([CH3:10])[CH2:7][CH2:8][N:9]=1.[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH3:11][CH:5]1[CH:6]([CH3:10])[CH2:7][CH2:8][NH:9][C:3](=[NH:13])[CH2:4]1
Reactant: [NH4+]
Reactant: COC1=NCCC(C)C(C)C1
Reactant: [Cl-]
Solvent: CO
Product: CC1CCNC(=N)CC1C
Product: Cl
Yield: 60.1 %

Procedure:
The product of EXAMPLE 123 (100 mg, 0.64 mmol) in 5 mL of MeOH was reacted with ammonium chloride (29.3 mg, 547 mmol) by the method of EXAMPLE 27 to yield 68 mg (66%) of the white solid title material.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][CH:6]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:7]=1[C:8]([O:10]C)=[O:9].C1COCC1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][CH:6]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 25.6 %

Procedure:
The product from Step 1 (2.32 g, 7.9 mmol, 1.00 equiv) was dissolved in MeOH (32 mL). THF (10 mL) was added, followed by 2.5N NaOH (10 mL). The reaction mixture was heated to 60° C. for 6 hours, then stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed again with 1N NaOH. The aqueous phases were combined and acidified to pH˜1 with 5N HCl. The aqueous solution was extracted twice with ethyl acetate. The combined organic extracts were washed with satd. NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated en vacuo and azeotroped several times with hexane. The resulting solid was triturated with 50% CH2Cl2/hexanes to afford 570 mg of the acid as an off-white solid. MS (ES+) m/e 282 [M+H]+.