Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C:7]([CH3:10])([CH3:9])[NH:6][C:5]1=[O:11].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][C:7]([CH3:9])([CH3:10])[NH:6][C:5]1=[O:11])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CN(CCO)C(=O)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CN(CCOS(C)(=O)=O)C(=O)N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(2-hydroxyethyl)-4,4-dimethylimidazolidin-2-one (5.9 g, 37 mmol) and pyridine (3.6 mL, 44.4 mmol) in 150 mL of anhydrous dichloromethane was added methanesulfonyl chloride (3.3 mL, 43 mmol). The reaction was stirred at room temperature for 20 hours, then diluted with 100 mL of dichlormethane and washed twice with 40 mL of 1 N HCl and once with brine. The organic fraction was dried over sodium sulfate and concentrated in vacuo to 3.54 g of the desired product as white solid. 1H NMR (CDCl3, 400 MHz) δ 1.33 (s, 6H), 3.06 (s, 3H), 3.23 (s, 2H), 3.54-3.57 (t, J=5.2, 2H), 4.36-4.39 (t, J=5.2 Hz, 2H); LRMS (ESI/APCI) m/z 237 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=2)[N:3]=1
Reactant: Cc1ccc(CO)nc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (5-methyl-pyridin-2-yl)methanol and DBU in DME. EI-MS m/e (%): 307 (M+, 76), 290 (28), 278 (16), 122 (100), 106 (78), 79 (30), 77 (38).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.[F:19][C:20]1[CH:21]=[C:22]([CH2:29][CH:30]=O)[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:30][CH2:29][C:22]4[CH:23]=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:20]([F:19])[CH:21]=4)[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Reactant: O=CCc1ccc([N+](=O)[O-])c(F)c1
Product: O=C1CN(CCc2ccc([N+](=O)[O-])c(F)c2)CCN1CCc1ccc2nonc2c1

Procedure:
The title compound was prepared from 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one and (3-Fluoro-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 414 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH:19]=[C:18]([S:21]([CH2:24][CH2:25][C:26](O)=[O:27])(=[O:23])=[O:22])[CH:17]=[CH:16]2)=[O:7].S(Cl)([Cl:36])=O>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH:19]=[C:18]([S:21]([CH2:24][CH2:25][C:26]([Cl:36])=[O:27])(=[O:23])=[O:22])[CH:17]=[CH:16]2)=[O:7]
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cccc(CCNC(=O)c3cccc(C(F)(F)F)c3)c2c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCS(=O)(=O)c1ccc2cccc(CCNC(=O)c3cccc(C(F)(F)F)c3)c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step B (3 mmol), dissolved in thionyl chloride, is stirred at 60° C. under a current of nitrogen for one hour. The thionyl chloride is evaporated off under reduced pressure and the residue is dried with the aid of a vane pump to yield the title product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[CH2:31]=O>>[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:31])[CH2:23][CH2:24]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: C=O
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Agent: Cl
Product: CN1CCC(COC[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide hydrochloride (200 mg, 0.44 mmol) and paraformaldehyde (134 mg, 4.4 mmol) afforded, after purification (SiO2: 2.5% isopropylamine in 10:2:2:DCM:EtOAc:hexane), 80 mg (42%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][N:14]([CH3:24])[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>Cl>[CH3:24][N:14]([CH3:13])[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][C:20]2([NH:1][C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=3[S:9](=[O:11])(=[O:10])[NH:12]2)[CH2:19][CH2:18]1
Reactant: CN(C)CCC1CCC(=O)CC1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Agent: Cl
Product: CN(C)CCC1CCC2(CC1)Nc1ccc(Cl)cc1S(=O)(=O)N2

Procedure:
A mixture of 2-amino-5-chlorobenzenesulfonamide (8.0 g., 0.039 mole) and 4-(2-dimethylaminoethyl)cyclohexanone (13.5 g., 0.08 mole) in 0.6 N ethanolic HCl (110 ml.) is heated at reflux 18 hours. The solvent is evaporated at reduced pressure and the residue dissolved in water (100 ml.) and neutralized with sodium hydroxide to precipitate 4'-(2-dimethylaminoethyl)-7-chlorospiro-[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxide hemisemihydrate which melts at 234°-5° C. after recrystallization from n-propanol.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:17])([C:14]([OH:16])=[O:15])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[O:22][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].[CH3:27]O>Cl>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([C:14]([O:16][CH3:27])=[O:15])([CH3:17])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Agent: Cl
Product: COC(=O)C1(C)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Reaction time: 3 h

Procedure:
In 5 ml of a saturated solution of hydrogen chloride in methanol was dissolved 0.20 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid at room temperature and the mixture was stirred for 3 hours, then the reaction solution was concentrated. The residue was purified on a short column of silica gel eluting with n-hexane containing 16% ethyl acetate to give 0.15 g of 4,6-di-t-butyl-5-hydroxy-2-methoxycarbonyl-2-methyl-2,3-dihydrobenzofuran as a colorless powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@:19]([CH3:25])([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][C@@:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:25])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)[C@@](C)(N)CO
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)[C@](C)(CO)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (R)-2-amino-2,3-dimethyl-butan-1-ol [CAN 155158-75-1] as starting materials, MS (EI): m/e=333.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].Cl>C1C=CC=CC=1>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc(NC(=O)CCl)c(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture consisting of 0.8 g of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid, 20 ml of dry benzene, and 0.5 ml of pyridine was added dropwise with stirring a solution of 0.4 ml of chloroacetyl chloride in 5 ml of benzene. The mixture was stirred overnight and then, shaken with dilute hydrochloric acid. The layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, dried over sodium sulfate, and evaporated. The residue was recrystallized from ethyl ether/n-hexane to give 0.65 g of 2-chloroacetylamino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid (m.p. 124°-125° C.).
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[F:15][C:16]([F:36])([F:35])[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[N:23]=[CH:22]2)=[O:18].Cl>CCOCC.C1COCC1>[F:36][C:16]([F:15])([F:35])[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[N:23]=[CH:22]2)([C:5]1[S:4][CH:3]=[N:7][CH:6]=1)[OH:18]
Reactant: C[Si](C)(C)c1nccs1
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1cncs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 2-trimethylsilanyl-thiazole (157 mg, 1.00 mmol) in dry ether (2 mL) was added n-BuLi (440 μL, 2.5 M in hexanes, 1.10 mmol). After 30 minutes, a solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (154 mg, 0.50 mmol) in dry ether (2 mL) was added. After 1 hour, the mixture was warmed to room temperature, quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl ether. The combined organic layers was washed with 10 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 202 mg of the crude product. To a solution of crude product (100 mg) in THF (2 mL) was added 2 M HCl (1 mL) and the mixture was stirred overnight. The mixture was then quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The mixture was purified over SiO2 using ethyl acetate-hexanes (0-100% gradient) to afford 38.4 mg (39% over two steps) of the title compound. MS m/z 394.26 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.CCN(C(C)C)C(C)C.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: Fc1cncc(Cl)c1I
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Fc1cncc(Cl)c1N1CCNCC1
Temperature: 120 °C

Procedure:
In a 100 mL sealed reaction vessel/bomb, 3-chloro-5-fluoro-4-iodo-pyridine (5600 mg, 21.75 mmol) was taken up in NMP (12 mL). To the resulting clear brown solution was added DIPEA (3.373 g, 4.546 mL, 26.10 mmol) followed by piperazine (2.810 g, 32.62 mmol). The vessel was sealed and heated thermally at 120° C. for 18 hrs. The mixture was allowed to cool to RT and was concentrated in vacuo to afford a brown gum which was purified by chromatography on silica, eluting with a gradient of DCM-DCM:MeOH:NH3(90: 10:1) 100-0 to 0:100. Fractions containing clean product were collected and concentrated in vacuo to afford 1-(3-chloro-5-fluoropyridin-4-yl)piperazine as a cream solid. (3.52 g, 75%). MS (ES+) 216.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH2:28][OH:29])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[O:21][CH3:22])=[C:6]([NH:23][C:24](=[O:26])[CH3:25])[CH:5]=1)[CH3:2].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:27][CH2:28][O:29][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[O:21][CH3:22])=[C:6]([NH:23][C:24](=[O:26])[CH3:25])[CH:5]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN(CCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2OC)c(NC(C)=O)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CCOS(=O)(=O)c1ccccc1)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2OC)c(NC(C)=O)c1
Reaction time: 2 h
Yield: 44 %

Procedure:
To a mixture composed of 16 g of Compound [1-g] and 70 ml of pyridine was added dropwise 13 g of benzenesulfonyl chloride under cooling with ice. The mixture was stirred at a temperature range between 10° C. and 15° C. for 2 hours and then the reaction solution was poured into cold diluted hydrochloric acid. The precipitate thus deposited was collected by filtration, washed with water and recrystallized from acetonitrile to obtain 9.5 g of Compound [1-h].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH:10](O)([CH3:12])[CH3:11]>>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(C)O
Reactant: Cc1cc(O)ncc1Br
Product: Cc1cc(OC(C)C)ncc1Br

Procedure:
The title compound was prepared from 5-bromo-2-hydroxy-4-methylpyridine and isopropanol in analogy to Example 9c): colorless liquid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35]CC4C=CC(OC)=CC=4)=[C:31]([Cl:45])[CH:30]=3)(=[O:28])=[O:27])=[CH:22][C:21]=2[CH3:46])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:45][C:31]1[CH:30]=[C:29]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH:17]3[CH2:18][CH2:19][NH:15][CH2:16]3)=[C:21]([CH3:46])[CH:22]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][C:32]=1[OH:35]
Reactant: COc1ccc(COc2ccc(S(=O)(=O)c3ccc(C4CCN(C(=O)OC(C)(C)C)C4)c(C)c3)cc2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)c2ccc(O)c(Cl)c2)ccc1C1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid was added to a solution of 3-{4-[3-chloro-4-(4-methoxy-benzyloxy)-benzenesulfonyl]-2-methyl-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared following the procedure described in Example 6) (0.397 g, 0.6939 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was then evaporated under reduced pressure. The crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.143 g of 2-chloro-4-(3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl)-phenol (white foam) that was transformed in the corresponding hydrochloride salt by addition of a small excess of HCl in 1,4-dioxane. The hydrochloride was recrystallized to afford 0.129 g of a white solid: MP=110.0-112.9° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([C@@H:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[C:7]([OH:16])[CH:6]=1.[CH3:17]O>>[CH3:17][O:13][C:12](=[O:14])[CH:11]([NH2:15])[C:10]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][CH:5]=1
Reactant: N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 50 mL of methanol cooled to 0° C. was dropwise added 3.75 mL of thionyl chloride foolowed by 5.0 g (0.030 mmol) of D-4-hydroxyphenylglycine. The reaction was heated to reflux for 5 h then stirred overnight at room temperature. The resulting mixture was concentrated in vacuo and the residue was diluted with ether. The resulting solid was collected by filtration and dried in vacuo to provide 5.9 g of amino-(4-hydroxy-phenyl)-acetic acid methyl ester as a white solid. Electrospray Mass Spec 182.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C@H:7]1[CH2:9][C@H:8]1[C:10](O)=[O:11])=O.O.[NH2:17][NH2:18]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:7]3[CH:8]([C:10](=[O:11])[NH:17][N:18]=2)[CH2:9]3)[CH:13]=[CH:14][CH:15]=1
Reactant: NN
Reactant: Nc1cccc(C(=O)[C@H]2C[C@H]2C(=O)O)c1
Solvent: O
Solvent: CCO
Product: Nc1cccc(C2=NNC(=O)C3CC23)c1
Yield: 60 %

Procedure:
600 mg (2.9 millimoles) of cis-2-(m-aminobenzoyl)-cyclopropanecarboxylic acid, 20 ml of ethanol and 0.16 g (3.2 millimoles) of hydrazine hydrate are refluxed for 6 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 0.35 g (60% of theory) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as colorless crystals, which are identical with the compound from Example 33.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[Cl:9][C:10]([Cl:14])([Cl:13])[CH:11]=O>C(#N)C>[Cl:9][C:10]([Cl:14])([Cl:13])[C@H:11]1[N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3](=[O:5])[O:4]1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C1O[C@@H](C(Cl)(Cl)Cl)N2CCC[C@H]12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To reactant (D)-Proline (4.6 g, 40 mmol) suspended in anhydrous acetonitrile (100 mL), was added 2,2,2-trichloroacetaldehyde (11.78 g, 80 mmol) slowly. The mixture was stirred at RT for 20 hour and was clear solution. After concentrated in vacuum, the residue was purified by CombiFlash on a 80 g silica gel column using EtOAC/Hexane as eluents to give (3S,7aR)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one 155a: 3.63 g, 37%. 1H NMR (400 MHz, Chloroform-d) δ 5.14 (s, 1H), 4.10 (dd, J=8.9, 4.7 Hz, 1H), 3.40 (ddd, J=10.9, 7.8, 6.0 Hz, 1H), 3.11 (dt, J=11.4, 6.0 Hz, 1H), 2.21 (dtd, J=13.0, 8.5, 6.8 Hz, 1H), 2.09 (ddt, J=12.7, 7.0, 5.2 Hz, 1H), 1.91 (ddq, J=12.4, 6.7, 5.7 Hz, 1H), 1.81-1.64 (m, 1H).
Reaction SMILES: [I:1][C:2]1[C:3]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[NH2:8].[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][N:4]=[C:3]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:2]=1[I:1])=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cnc(C2CCOCC2)c(I)c1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1cnc(C2CCOCC2)c(I)c1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a stirred solution of 725 mg (2.17 mmol) 3-iodo-5-methoxy-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine in 14 ml acetone was added dropwise 0.35 ml (2.60 mmol) benzoyl isothiocyanate at room temperature. The reaction mixture then heated at reflux for 2 h before being cooled to room temperature concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 868 mg (80%) 1-benzoyl-3-[3-iodo-5-methoxy-2-(tetrahydro-pyran-4-yl)-pyridin-4-yl]-thiourea as a white crystalline solid. ES-MS m/e (%): 498 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:7]=1.[Cl:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([CH2:10][Cl:11])=[CH2:9])[CH:7]=1
Reactant: C=C(C)c1cncc(Br)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1cncc(Br)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 26.7 %

Procedure:
A mixture of 7.12 g of 3-bromo-5-isopropenylpyridine, 6.85 g of N-chlorosuccinimide and 15 ml of carbon tetrachloride was stirred at 80° C. for 7 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered out. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane 1:19) to obtain 2.23 g of the objective compound.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]([F:26])([F:25])[O:11][C:12]1[CH:17]=[CH:16][C:15](C2C=CC(O)=CC=2)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:25])[F:26])=[CH:17][CH:16]=2)=[N:7][CH:6]=1
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2ncc(Br)cn2)cc1
Yield: 75.2 %

Procedure:
A mixture of 5-bromo-2-iodopyrimidine (88) (1.50 g, 5.27 mmol), 4-(trifluoromethoxy)phenylboronic acid (44) (1.185 g, 5.75 mmol) and Na2CO3 (1.11 g, 10.5 mmol) in toluene (120 mL) and water (15 mL) was purged with N2. Pd(PPh3)4 (60 mg, 0.05 mmol) was added and the mixture was refluxed under N2 for 17.5 h, then partitioned between EtOAc and water. Column chromatography of the organic portion on silica gel (eluting with 4:1 hexanes/CH2Cl2) gave 5-bromo-2-[4-(trifluoromethoxy)phenyl]pyrimidine (89) (1.264 g, 75%) as a white solid: mp 107-108° C.; 1H NMR (CDCl3) δ 8.83 (s, 2H), 8.46 (d, J=9.0 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H). APCI MS m/z 319, 321 [M+H]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:32][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[O:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[O:30][CH3:31])[C:9]=2[C:8]=1[CH3:33])=[O:6].Cl>CO.C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:9]3[C:8]([CH3:33])=[C:7]([C:5]([OH:6])=[O:4])[S:32][C:10]=3[N:11]=[CH:12][N:13]=2)=[C:17]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[O:30][CH3:31])[CH:18]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCC[C@@H]3OC)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@H]1CCCC[C@@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12

Procedure:
7 ml sodium hydroxide solution (2M) were added to a mixture of 1.270 g 4-[4-fluoro-2-((1S,2S)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (cpd. 42.1) in 10 ml MeOH/THF (1:1). The reaction mixture was stirred at reflux for 15 minutes, then cooled and acidified with 2 M aq. HCl. The solvent was removed in vacuo, the residue suspended in water, filtered and dried.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14](OC)=[O:15])[CH:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O>[CH2:1]([N:8]1[CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH:10]([CH2:14][OH:15])[CH2:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1c1cccc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(C2C(CO)CC(=O)N2Cc2ccccc2)c1
Temperature: 50 °C

Procedure:
To 42.1 gm. of methyl 1-benzyl-2-(3-methoxyphenyl)-5-oxopyrrolidin-3-carboxylate in 436 ml. of absolute methanol was slowly added at -10° to -5°, 37.9 gm. of sodium borohydride. The reaction mixture was left in the ice bath until it came to ambient temperature. Concentration in vacuo provided a white gum which was suspended in water and heated to 50° C. The gum was extracted with chloroform, dried (Na2SO4), filtered, and concentrated in vacuo to yield 22.8 gm. of yellow oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+].Cl>>[NH2:14][C:15]1[CH:16]=[CH:17][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[CH2:12][C:13]([OH:18])=[O:19]
Reactant: [OH-]
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Agent: Cl
Agent: [Na+]
Product: Nc1ccc(C(=O)c2ccccc2)cc1CC(=O)O

Procedure:
A mixture of 1.0 g. (0.004 mole) of 5-benzoylindolin-2-one and 30 ml. of 3N sodium hydroxide was refluxed for 0.5 hour. The reaction mixture was cooled, acidified to pH 6 with 3N hydrochloric acid and slightly acidic solution was extracted with chloroform. The chloroform extracts were dried (magnesium sulfate) and concentrated to a solid. Recrystallization from ethanol-water gave 0.9 g. (84.5%) of pure product which melted at 143°-145° C.