Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[N:9][N:8]=[C:7]1[SH:11].[CH3:16]I.C[O-].[Na+]>CO>[F:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([F:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[N:9][N:8]=[C:7]1[S:11][CH3:16]
Reactant: Fc1cc(F)cc(Cn2cnnc2S)c1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1nncn1Cc1cc(F)cc(F)c1

Procedure:
The reaction of 4-(3',5'-difluorobenzyl)-1,2,4-triazole-3-thiol (prepared as in Example 3) with methyl iodide and sodium methoxide in methanol by known techniques yields 4-(3',5'-difluorobenzyl)-3-methylthio-1,2,4-triazole.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[F:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=1.[OH-].[K+]>C(O)C.O>[O:5]1[CH2:4][CH:3]1[CH2:1][O:16][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][C:11]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(F)ccc1OCC1CO1
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Epichlorohydrin (38 g) was added to a stirred solution of 5'-fluoro-2'-hydroxyacetophenone (20.9 g) in ethanol (20 ml). A solution of potassium hydroxide (9.5 g) in a mixture of ethanol (30 ml) and water (5 ml) was then added and stirring continued for one hour. The solvent was removed in vacuo and the residue poured into water then extracted with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by chromatography on silica, eluting with a 9:1 mixture, then a 3:2 mixture, of petroleum ether (b.p. 40-60° C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give 2'-(2,3-epoxypropoxy)-5'-fluoroacetophenone (4.68 g) as an oil.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([Sn](C)(C)C)=[CH:6][C:5]=1[O:16][CH3:17])(=[O:3])[CH3:2].Cl[C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:37])[CH2:26][CH2:27][N:28]([C:30]2[CH:31]=[CH:32][C:33](Cl)=[N:34][CH:35]=2)[CH3:29])=[CH:21][N:20]=1.[F-].[K+]>C1(C)C=CC=CC=1.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>[C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:19]2[CH:24]=[CH:23][C:22]([N:25]([CH3:37])[CH2:26][CH2:27][N:28]([C:30]3[CH:31]=[CH:32][C:33]([C:7]4[CH:6]=[C:5]([O:16][CH3:17])[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([O:10][CH3:11])[CH:8]=4)=[N:34][CH:35]=3)[CH3:29])=[CH:21][N:20]=2)=[CH:6][C:5]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc([Sn](C)(C)C)cc(OC)c1C(C)=O
Reactant: CN(CCN(C)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(C(C)=O)c(OC)c4)nc3)cn2)cc(OC)c1C(C)=O
Temperature: 130 °C
Reaction time: 22 h
Yield: 23 %

Procedure:
Under nitrogen, to a solution of (4-acetyl-3,5-dimethoxyphenyl)trimethyltin (235.0 mg, 0.760 mmol) synthesized as described in Reference Example 8 in toluene (10 mL) were added crude N,N′-bis(2-chloro-5-pyridyl)-N,N′-dimethylethylenediamine(78.0 mg, approx. 0.25 mmol) synthesized as described in Reference Example 9 and tetrakis(triphenylphosphine)palladium (116.0 mg, 0.100 mmol). After stirring at 130° C. for 22 hours, a saturated aqueous potassium fluoride was added to the reaction mixture and the mixture was stirred for 1 hour. Insoluble materials were removed by filtration through Celite. The residue was washed with chloroform, and the aqueous layer of the filtrate was extracted with chloroform. The washing and the organic layer of the filtrate were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield N,N′-bis[2-(4-acetyl-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethylethylenediamine as a pale yellow crystalline powder [41.4 mg, yield: 23% based on N,N′-bis(2-hydroxy-5-pyridyl)-N,N′-dimethylethylenediamine ditrifluoroacetate].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.FC(F)(F)[C:13]([O:15]C(=O)C(F)(F)F)=[O:14].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=[O:14]
Reactant: Clc1cccc2cc[nH]c12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c2c(Cl)cccc12
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of 7-chloroindole (7.1 g, 47.0 mmol) in dimethylformamide (60 ml) was cooled to 5° C. under nitrogen and trifluoroacetic anhydride (7.6 ml, 54.0 mmol) was added over 10 mins, maintaining the temperature below 10° C. The mixture was stirred at 5-10° C. for 2 h, then poured into water (600 ml). The resulting suspension was stirred for 15 mins and the 7-chloro-3-[(trifluoromethyl)carbonyl]-1H-indole precipitate was filtered off, washing with water to neutrality. The damp solid was suspended in 4 M aqueous sodium hydroxide (500 ml) and heated to reflux with stirring for 1 h. The mixture was cooled and washed with diethyl ether (2×100 ml). The aqueous phase was then acidified to pH 1 using 5 M hydrochloric acid and the resulting fine precipitate filtered off, washed with water to neutrality and dried to afford 7-chloro-1H-indole-3-carboxylic acid as a pink solid (7.5 g, 38.0 mmol).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[CH3:6][CH:7]([C:13](OCC)=[O:14])[C:8](OCC)=[O:9].C[O-].[Na+]>C(O)C>[NH2:4][C:3]1[N:5]=[C:8]([OH:9])[C:7]([CH3:6])=[C:13]([OH:14])[N:2]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(N)nc1O
Temperature: 65 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a stirred mixture of guanidine hydrochloride (1.91 g, 20.0 mmol) and diethyl methylmalonate (3.48 g, 20.0 mmol) in ethanol (30 ml) was added sodium methoxide (2.7 g, 50.0 mmol, 25% in methanol) dropwise. The cloudy mixture was stirred at 60-70° C. for 16 hours. After evaporation of volatiles under reduced pressure, the residue was treated with 1.0 M hydrochloric acid until pH=2. Filtration and drying provided 2-amino-4,6-dihydroxy-5-methyl-pyrimidine (2.5 g, 90% yield) as a white powder.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([S:16](Cl)(=[O:18])=[O:17])[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13].C([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=O.C(N(CC)CC)C>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([S:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:18])=[O:17])[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(S(=O)(=O)Cl)cc(OC)c1OC
Reactant: O=CN1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)N2CCNCC2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
75 ml of a methylene chloride solution containing 7.40 g of 3,4,5-trimethoxybenzenesulfonyl chloride were dropped into 150 ml of a methylene chloride solution containing 3.80 g of N-formylpiperazine and 7.73 ml of triethylamine in an ice bath. The mixture was then stirred for 30 minutes at 0° to 5° C., after which it was poured into water and extracted twice with methylene chloride. The combined methylene chloride extracts were washed with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure. The residue (9.86 g) was dissolved in a mixture of 150 ml of tetrahydrofuran, 75 ml of methanol and 50 ml of a 10% w/v aqueous solution of sodium hydroxide, and then stirred for 14 hours at room temperature. At the end of this time, the reaction solution was poured into water and extracted 4 times with methylene chloride. The combined methylene chloride extracts were washed with water, dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure. The residue was crystallized from a mixture of hexane and ethyl acetate, to give 7.02 g of the title compound as crystals, melting at 131° to 133° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.Cl[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=1>>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8][O:9][C:10]=3[C:11]([F:14])([F:12])[F:13])[N:3]=[CH:2]2)=[N:23][CH:24]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 76 %

Procedure:
As described for Example 4, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (450 mg, 0.1.6 mmol) was converted, using methyl 6-chloronicotinate instead of 4-fluorobenzotrifluoride, to the title compound (510 mg, 76%) which was obtained as a white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][CH:23]([F:31])[C:24]1[S:28][CH:27]=[C:26]([CH2:29][OH:30])[CH:25]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:26]5[CH:25]=[C:24]([CH:23]([F:31])[F:22])[S:28][CH:27]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Reactant: OCc1csc(C(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)F)c4)cc3=O)cn12
Temperature: 100 °C
Yield: 51.6 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (100 mg), (5-(difluoromethyl)-3-thienyl)methanol (88 mg), potassium tert-butoxide (109 mg) and toluene (3 ml) was heated at 100° C. for 1 h. The reaction mixture was then cooled to room temperature, poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-IPE to give the title compound (64.1 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:32])[C:9]=3[C:8]2=[O:33])=[CH:4][CH:3]=1.[C:36]([O-])([O-])=O.[K+].[K+].CI.O>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:36])[C:9]=3[C:8]2=[O:33])=[CH:34][CH:35]=1
Reactant: CC(C)[Si](Oc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O)(C(C)C)C(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O

Procedure:
A mixture of 12 from the monosilylation reaction was heated at 40° C. in anhydrous acetonitrile with K2CO3 (1.64 g, 11.8 mmol) and methyl iodide (4.2 g, 29.6 mmol) for 5 hours. The reaction mixture was worked up by addition of H2O and EtOAc. The organic layer was washed with H2O and the solvent was removed in vacuo. The residue was purified by column chromatography using a gradient of 10% EtOAc-Hex to elute the product 13 as a yellow solid (72% for two steps). 1H NMR (300 MHz, CDCl3) δ 1.13 (d, 18H, J=8 Hz), 1.53 (septet, 3H, J=7 Hz), 4.29 (s, 3H), 4.84 (s, 2H), 7.00 (t, 2H, J=8 Hz), 7.48 (dd, 2H, J=5, 8 Hz), 7.58 (dd, 1H, J=4, 8 Hz), 8.65 (dd, 1H, J=2, 8 Hz), 8.93 (dd, 1H, J=2, 4 Hz); EI MS (m/z) 509.7 [MH+], 531.4 [M+Na].
Reaction SMILES: C([O:4][C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH2:15][CH2:16][O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:25]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17][CH2:16][CH2:15][N:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([OH:4])[C:14]=3[O:13][CH2:12][CH2:11]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)Oc1cccc2c1OCCN2CCOC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cccc2c1OCCN2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
8-acetoxy-4-(2-(diphenylmethoxy)ethyl)-3,4-dihydro-2H-1,4-benzoxazine (482 mg) was dissolved in THF (2 ml) and a methanol (10 ml), and anhydrous potassium carbonate (250 mg) was added to the resultant solution, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was poured into 5% citric acid, and then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated to obtain the colorless oily object compound (429 mg, yield 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([O:9][CH3:10])([CH3:8])[C:4](=[N:6][OH:7])[CH3:5].C([Li])CCC.[CH3:16][Si:17]([CH3:31])([CH3:30])[C:18]#[C:19][CH2:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[OH:25][CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[O:21][CH2:20][C:19]#[C:18][Si:17]([CH3:16])([CH3:31])[CH3:30])[CH2:5][C:4](=[N:6][OH:7])[C:3]([O:9][CH3:10])([O:2][CH3:1])[CH3:8]
Reactant: C[Si](C)(C)C#CCOc1ccccc1C=O
Reactant: COC(C)(OC)C(C)=NO
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(C)(OC)C(CC(O)c1ccccc1OCC#C[Si](C)(C)C)=NO
Reaction time: 0.08 h
Yield: 127.2 %

Procedure:
To a solution of 3,3-dimethoxybutan-2-one oxime (270 mg) in tetrahydrofuran (2.7 ml) was added dropwise, at 0° C. under argon, n-butyllithium (2M in tetrahydrofuran, 1.83 ml). After stirring for a further 5 minutes, a solution of 2-{[3-(trimethylsilyl)prop-2-yn-1-yl]oxy}benzaldehyde (232 mg) in tetrahydrofuran (1 ml) was added dropwise to the reaction mixture, which was stirred for a further 1 hour. Subsequently, concentrated ammonium chloride solution was added to the reaction mixture, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 1-hydroxyl-4,4-dimethoxy-1-(2-{[3-(trimethylsilyl)prop-2-yn-1-yl]oxy}phenyl)pentan-3-one oxime (482 mg, 69%).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:20]#[N:21].Cl>CN(C)C=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[S:10][C:6]3[C:7](=[C:2]([C:20]#[N:21])[CH:3]=[CH:4][CH:5]=3)[N:8]=2)=[CH:12][CH:13]=1
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2nc3c(Br)cccc3s2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(C#N)cccc3s2)cc1

Procedure:
To a solution of EXAMPLE 1C (5 g) in N,N-dimethylformamide (1.6 mL) was added copper(I) cyanide (2.1 g) and the mixture heated at reflux for 6 hours. The mixture was cooled, poured into 1N hydrochloric acid and extracted with ethyl acetate. The solid that precipitated out of the organic layer was filtered, washed with water and dried to afford the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]1[CH2:8][C@@H:7]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:21][C:18]1[CH:17]=[N:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C@H:7]3[CH2:8][C@H:6]3[CH2:5][CH2:4][NH2:1])[CH2:10][CH2:11]2)=[N:20][CH:19]=1
Reactant: [N-]=[N+]=NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{4-[(1S,2S)-2-(2-azidoethyl)cyclopropyl]piperidin-1-yl}-5-chloropyrimidine (34 mg, 0.11 mmol) from step 2 of this example was dissolved in THF (1 mL), triphenylphosphine (58.1 mg, 0.22 mmol) was added, then water (0.085 mL). The reaction was run at room temperature for 1 hour, then 40° C. 1 hour. The reaction was cooled down to room temperature, concentrated to dryness and purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 10% methanol/dichloromethane to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([N:17]2[CH2:16][CH2:15][C:14]3([CH2:20][CH2:21][N:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:9])=[O:10])[CH2:12][CH2:13]3)[C:18]2=[O:19])=[CH:27][CH:26]=1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: COC(=O)c1ccc(I)cc1
Product: COC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 4-iodo-benzoic acid methyl ester White solid. MS (ESI): 463.1 MH+).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COc1cccc2c1CCCC2CN1CCCCC1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc2c1CCCC2CN1CCCCC1
Temperature: 0 °C

Procedure:
A solution of the 5-methoxy compound from step 4 above (41 g), 47-49% hydrobromic acid (410 ml) in glacial acetic acid (410 ml) is stirred at reflux under nitrogen for 2.5 hours. The cooled reaction mixture is poured into ice/water, made alkaline and the pH adjusted until no more cloudiness appears. The resulting oil is extracted into ether, washed, dried, filtered and the filtrate evaporated in vacuo forming a solid residue which is recrystallized from hot acetonitrile yielding the desired product as a crystalline solid, M.P.=129°-131° C.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:51]([C:56](O)=[O:57])=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:59](N1C=CN=C1)([N:61]1[CH:65]=[CH:64][N:63]=[CH:62]1)=O.CN(C)CCN>C1COCC1>[CH3:59][N:61]([CH3:62])[CH2:65][CH2:64][NH:63][C:56]([C:51]1[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: O=C(O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Yield: 85.1 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (2-dimethylamino-ethyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.8 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1′-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) and warmed as described. The reaction was allowed to cool and then treated with N,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq.). The reaction was treated as described in example 1 to give an orange/brown oil. The oil was purified by silica gel flash chromatography using 10% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl 2-carboxylic acid (2-dimethylamino-ethyl)-amide (0.81 g, 85% yield) as a faint yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=3[N:9]=[C:10]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Oc1ccc([N+](=O)[O-])cc1NC2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(s1)Oc1ccc([N+](=O)[O-])cc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2-methyl-7-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2-methyl-4-(4-methylpiperazin-1-yl)-7-nitrothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(F)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (45 mg, 0.20 mmol) was dissolved in 3 mL of CH2Cl2, treated with 4-fluorophenylisocyanate (28 μL, 0.24 mmol), and stirred at room temperature overnight. The compound of interest precipitated out of solution and was filtered and washed with CH2Cl2 to afford Compound 31 as a white solid, 56 mg, 77% yield: LCMS m/z (%)=359 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.12 (s, 1H), 8.08 (s, 1H), 7.63 (ddd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.54 (m, 2H), 7.48 (d, J=2.8 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.05 (dd, J1=9.0 Hz, J2=9.0 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −123.08 (m, 1F), −177.41 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([O:18]C)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnn(-c2ccc(Cl)cc2)c1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
A mixture of methyl 1-(4-chlorophenyl)-5-isopropyl-pyrazole-4-carboxylate (26.0 g, 96.7 mmol) and lithium hydroxide monohydrate (10.0 g, 238 mml) in MeOH (60 mL), THF (60 mL), and H2O (30 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, acidified with 1 N aqueous HCl, and extracted with EtOAc (600 ml). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield 1-(4-chlorophenyl)-5-isopropylpyrazole-4-carboxylic acid (24.0 g, 97%).