Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Product: O=C(O)CCc1ccc(OCc2cccc(N(Cc3ccccc3)c3ccccc3)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 302 from methyl 3-[4-[(3-anilinobenzyl)oxy]phenyl]propanoate and benzylbromide. colorless crystals (yield 74%). MS (APCI−): 436 (M−H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:8][CH:7]=1.[H-].[Na+].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[N:27]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)=[CH:8][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(OCCCBr)cc2)C1
Reactant: C1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(OCCCN3CCCC3)cc2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
tert-Butyl (2S)-2-(4-(3-bromopropyloxy)phenyl)morpholine-4-carboxylate (2.0 g, 5.0 mmol) was added to a solution of sodium hydride (60% in oil, 0.22 g, 5.50 mmol) and pyrrolidine (0.43 g, 6.05 mmol) in tetrahydrofuran (40 ml) at room temperature and the mixture was stirred at 80° C. for 5 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish tert-butyl (2S)-2-(4-(3-(pyrrolidin-1-yl)propyloxy)phenyl)morpholine-4-carboxylate (1.13 g, 58%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].[N:21]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23](O)[N:22]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][C:23]1[N:22]=[N:21][C:26]([OH:27])=[CH:25][CH:24]=1)=[O:5])[CH3:2]
Reactant: Oc1ccc(O)nn1
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccc(O)nn1

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 5, from (1R,2R)-4-(tert-butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, Example 69, Step 4) and pyridazine-3,6-diol to afford the desired product as a white gum. MS (EI): 385.3 (M−H)−.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([Br:14])=[CH:9][C:8]=1[CH3:15].[C:16](=[O:18])=[O:17].Cl>CCCCCC>[Br:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH3:15])[CH:9]=1
Reactant: O=C=O
Reactant: Cc1cc(Br)c(C)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)c(C)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −78° C., 100 ml (0.16 mol) of a 1.6 molar n-butyl lithium solution in hexane is added dropwise to a solution of 43.63 g (0.162 mol) of 2,5-dibromo-p-xylene, and stirred for one hour. Then dry carbon dioxide is passed into the solution for 4 hours. It is slowly heated to ambient temperature and stirred for 16 hours. After the slow addition of 210 ml of 2N hydrochloric acid, the phases are separated, the aqueous phase is extracted 2× with 200 ml ether, the combined organic phases are washed with conc. NaCl solution and dried with Na2SO4. After the solvent has been eliminated in vacuo the crude product is mixed with 200 ml of 2N NaOH and the brown solution obtained is extracted 3× with 100 ml of diethyl ether. The aqueous phase is acidified with conc. HCl and the precipitate which then forms is suction filtered, washed with ice water and dried.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[O:20])[CH2:12][C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[CH3:19]
Reactant: CC(=O)/C=C/c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1
Yield: 87.1 %

Procedure:
Using the procedure of Example 2, sodium pellets (6.33 g, 0.275 mol), (E)-4-(4-chlorophenyl)-but-3-en-2-one (45.16 g, 0.25 mol) and diethyl oxalate (43.8 g, 0.30 mol) were reacted to give (E)-6-(4-chlorophenyl-2,4-dioxo-hex-5-enoic acid ethyl ester (4; 61.1 g, 87%) as yellow crystals: mp 117-118° C.; 1H NMR (400 MHz, CDCl3) δ 14.80 (s, 1H), 7.68 (d, J=15.9 Hz, 1H), 7.53-7.35 (m, 4H), 6.62 (d, J=15.9 Hz, 1H), 6.53 (s, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H13ClO4, 280.050. found, 280.050.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C[Si]([C:17]#[CH:18])(C)C>N1C=CC=CC=1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)#[CH:18]
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)CCC(=O)N2
Reaction time: 18 h

Procedure:
A mixture of 8.0 g of 6-bromo-3,4-dihydrocarbostyril, 6.95 g of trimethylsilylacetylene, 460 mg of bis(triphenylphosphine)palladium dichloride and 62 mg of cuprous iodide in 53 ml of pyridine and 11 ml of triethylamine was refluxed for 3 days. The solvent was removed under reduced pressure, 50 ml of methanol added along with 300 mg of potassium carbonate, and the mixture stirred under nitrogen for 18 hours. The solvent was removed under reduced pressure and the residue chromatographed on silica gel, eluting with 3% methanol in methylene chloride, giving a product of 6-ethynyl-3,4-dihydrocarbostyril, m.p. 182°-184° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH:24]=[CH:23][C:22](=[O:25])[O:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[Si:1]([O:18][CH2:19][C@H:20]1[O:21][C:22](=[O:25])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1C=CC(=O)O1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@@H]1CCC(=O)O1)(c1ccccc1)c1ccccc1
Yield: 95.2 %

Procedure:
A solution of (25)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-2H-furan-5-one (compound 40c, 2.8 g, 8.0 mmol) in EtOAc (40 mL) was stirred with 10% palladium on carbon (280 mg) under hydrogen atmosphere overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo to afford 2.7 g of (5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-2-one (compound 40d) as a viscous oil. MS obsd. (ESI+) [(M+H)+]: 355.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([OH:13])([P:9]([OH:12])([OH:11])=[O:10])[C:6]([OH:8])=[O:7])#[N:2].[H][H]>N.[Rh]>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]([OH:13])([P:9]([OH:12])([OH:11])=[O:10])[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: N#CCCC(O)(C(=O)O)P(=O)(O)O
Agent: [Rh]
Agent: N
Product: NCCCC(O)(C(=O)O)P(=O)(O)O

Procedure:
The hydrogenation of 4-cyano-2-hydroxy-2-phosphonobutanoic acid is carried out using the hydrogenation technique of Freifelder (J. Am. Chem. Soc., 82 2386 (1960)). The cyano compound (2.09 g; 0.01 mole) is placed in 20 ml of 10% methanolic ammonia. Rhodium on alumina (5%) catalyst (0.5 g) is added, and the mixture is hydrogenated at 40 PSI on a Parr apparatus for several hours (until uptake of hydrogen is complete). The catalyst is filtered of and the filtrate is evaporated dry. The residue treated with cation exchange resin in H+ form to convert the material to acid form. The solution containing it is evaporated to dryness under vacuum. The product is purified by dissolving the residue in water, adding ethanol to give a precipitate, and collecting the solids by filtration. Further purification is accomplished by again recrystallizing from water/ethanol.
Reaction SMILES: [CH:1]1([Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1(O)[CH2:17]C[CH2:15][CH2:14]1.C[Si](C)(C)Cl>C[O-].[Na+]>[CH:10]1([O:9][Si:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)([O:11][CH3:12])[O:7][CH3:8])[CH2:15][CH2:14][CH2:13][CH2:17]1
Reactant: CO[Si](OC)(OC)C1CCCC1
Reactant: OC1CCCC1
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CO[Si](OC)(OC1CCCC1)C1CCCC1
Yield: 85.1 %

Procedure:
In a 50 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 5.0 g (0.0262 mole) of cyclopentyl trimethoxysilane, 22.5 g (0.262 mole) of cyclopentyl alcohol and 18.6 mg (0.34 m mole) of sodium methoxide, which were then reacted with each other at room temperature for 2 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 5.4 g (0.0223 mole) of cyclopentyloxy cyclopentyl dimethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(CC(C#N)(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Oc1ccccc1
Product: N#CC(CC1CCCNC1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A mixture of α,α-bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-3-piperidinepropanenitrile (41.21 g, 0.0858 mole) and phenol (100 g, 1.06 mole) was heated at reflux for 2 hours. the reaction mixture was cooled to room temperature and made alkaline with ice and 50% sodium hydroxide. The aqueous layer was extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide. The organic layer was then dried over sodium sulfate and filtered and solvent was removed to give a dark brown oil. This oil was subjected to flash chromatography on silica gel using methanol for elution. Fractions of similar purity were combined and solvent removed. The oil obtained was dried in vacuo overnight at 80° C., to give 18.83 g (67.2% yield) of brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([N:23]=[N+:24]=[N-:25])[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(Cl)ncn2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(N=[N+]=[N-])ncn2)cc1
Temperature: 80 °C

Procedure:
A suspension of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (see Example 117) (1.1 g, 3.44 mmol) and sodium azide (0.31 g, 4.81 mmol, 1.4 equiv) in DMF (13 mL) is heated to 80° C. for 2.5 h. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is diluted with EtOAc (25 mL) and H2O (66 mL). The layers are separated and the aqueous layer is extracted with EtOAc (2×40 mL and 2×50 mL). The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel (80 g) column chromatography CH2Cl2/Et2O, 90/10). The title compound is obtained as a white solid: ES-MS: 327.0 [M+H]+; single peak at tR=7.42 min (System 2); Rf=0.26 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[N:15]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:16]2[O:17][C:18]=1[CH3:19].CN([CH:27]=[O:28])C>>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[N:15]2[N:22]=[C:21]([CH3:23])[C:20]([CH:27]=[O:28])=[C:16]2[O:17][C:18]=1[CH3:19]
Reactant: Cc1cc2oc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To DMF (12 ml) is added POCl3 (1.326 ml, 14.23 mmol) dropwise at RT. After 10 mins 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (Intermediate HE) (2.00 g, 7.11 mmol) is added. The reaction is stirred at RT for 16 hours. On cooling to 0° C. the reaction mixture is quenched with 1M HCl and added in portions to sat. Na2CO3 (100 ml). The product is extracted with EtOAc (2×100 ml) and the combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting solid is recrystallised from EtOAc/iso-hexane to afford the title compound as a pale yellow solid. MS: m/z 309.10 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][C:42]([CH:45]3[CH2:47][CH2:46]3)=[CH:43][CH:44]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][C:42]([CH:45]3[CH2:46][CH2:47]3)=[CH:43][CH:44]=2)[CH:34]=1)=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Product: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J35) (251 mg, 0.75 mmol) and 3-[3-(6-cyclo-propyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (372 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([CH2:24][OH:25])[CH:3]=1.[C:26](N1C=CN=C1)([N:28]1C=CN=[CH:29]1)=[O:27].CN>ClCCl>[CH3:29][NH:28][C:26](=[O:27])[O:25][CH2:24][C:4]1[CH:3]=[C:2]([CH3:1])[N:6]([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:22])([F:23])[F:21])[CH:10]=[CH:11][CH:12]=2)[N:5]=1
Reactant: Cc1cc(CO)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)OCc1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n1
Reaction time: 8 h
Yield: 97 %

Procedure:
To the solution of the alcohol from EXAMPLE 123 (0.050 g, 0.14 mmol) in dry dichloromethane (3 mL) was added 1,1′-carbonyldiimidazole (0.023 g, 0.14 mmol). The reaction solution was stirred at room temperature for one hour before the methylamine was added. The reaction was then stirred at the same temperature for overnight. The reaction was quenched with 10% HCl aqueous, and extracted with dichloromethane (3 times). The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The product was purified via a column chromatography on silica gel. The carbamate was obtained as a white solid, 0.0565 g, 97% yield.
Reaction SMILES: [OH-].[Na+].[C:3]([O:18]CC)(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16].Cl>CO>[C:3]([OH:18])(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16]
Reactant: CCOCCSCCCCCCCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCCSCCCCCCCC(=O)O
Reaction time: 7 h

Procedure:
NaOH (1M, 24 mL, 24 mmol) was added to a solution of the above ethyl 9-thia-12-oxatetradecanoate. (6.8 mmol) in MeOH (20 mL). After stirring for 7 h, the reaction mixture was acidified with 10% HCl (pH 1) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water (50 mL), brine (50 mL), and dried (Na2SO4). The crude product was recrystallized from hexane to afford the title compound, 9-thia-12-oxatetradecanoic acid; yield 92%; bp 134°-136° C./0.005 torr; IR (neat): 3000 (broad) and 1735 cm-1NMR: 1.23 (3H, t, J=7.2 Hz), 1.28-1.46 (6H, m), 1.53-1.68 (4H, m), 2.35 (2H, t, J=7.3 Hz), 2.54 (2H, t, J=7.1 Hz), 2.70 (2H, t, J=7.1 Hz), 3.52 (2H, q, J=7.2 Hz), 3.60 (2H, t, J=6.9 Hz), and 8.85 ppm (1H, br s); Found: C, 57.96, H, 9.77%. Calcd for C12H24SO3 : C, 58.03, H, 9.74%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:35]O)[C:22]1[C:31]([O:32][CH3:33])=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:34])[CH:23]=1>>[F:34][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:35]=2)[C:31]([O:32][CH3:33])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cc(OC)c(C(N)=NO)cc1F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cc(F)c(C(=O)OC)cc3OC)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (78.31 mg; 0.31 mmol) and Intermediate 57 (74 mg; 0.31 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1). The white solid was washed with MeOH affording the title compound as an off-white powder. LC/MS (Method B): 463.2 (M+H)+. HPLC (Method A) Rt 6.16 min (Purity: 97.9%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.Br[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)CC>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[O:11][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:12]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Solvent: CCC#N
Product: CCOC(=O)c1coc(-c2ccc(OCCCCl)cc2)n1
Reaction time: 24 h
Yield: 41 %

Procedure:
A mixture of 4-(3-chloropropoxy)benzamide ax54 (3.55 g, 16.6 mmol, 1 eq) and ethyl bromopyruvate (3.24 g, 16.6 mmol, 1 eq) in propionitrile (60 ml) is heated at reflux. After 24 h, the solvent is evaporated, and the residue is taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/hexane 90:10) affords 2.12 g of ethyl 2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-4-carboxylate i33.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CCOC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OCC)C3)cc1

Procedure:
Method as example 34 using 1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and ethyl chloroformate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[O:11][C:12](=O)[C:13]1[C:18]([I:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:20][C:16]1[CH:15]=[C:14]2[C:13](=[C:18]([I:19])[CH:17]=1)[C:12](=[O:11])[N:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:21]2
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A mixture of 4-chloro-benzyl amine (1.3 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.374 g, 1.0 mmol), and K2CO3 (0.277 g, 2 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.204 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.15 (s, 2H), 4.74 (s, 2H), 7.10 (d, 1H), 7.23-7.33 (m, 4H), 7.67 (d, 11H). GC-MS: m/z 401 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:17]([N:20]=[C:21]=[S:22])(=[O:19])[CH3:18]>C(OCC)C>[C:17]([NH:20][C:21](=[S:22])[NH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])(=[O:19])[CH3:18]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: CC(=O)N=C=S
Solvent: CCOCC
Product: CC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of 3,4-diaminobenzophenone (8.48 g.; 0.04 mole) in ethyl ether (1.0 L.) there is added dropwise acetyl isothiocyanate (4.04 g.; 0.04 mole). The solution is stirred at room temperature for two hours and a precipitate collected by filtration and dried to afford 10.7 g. (85% yield) of 3-(3-acetylthioureido)-4-aminobenzophenone, m.p. 211° C., dec.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[CH:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][S:19]([CH2:22][CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])(=[O:21])=[O:20])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]>>[CH:9]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:2][C:3]2[CH:7]=[C:6]([CH3:8])[O:5][N:4]=2)[S:19]([CH2:22][CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])(=[O:20])=[O:21])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]
Reactant: Cc1cc(CCl)no1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: Cc1cc(CN(C2CCN(C(C)C)CC2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)no1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-(5-methyl-isoxazol-3-ylmethyl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 67 mg (1 equiv.) 3-chloromethyl-5-methyl-isoxazole and 200 mg (0.50 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide (reaction temperature: 60° C.). Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-(5-methyl-isoxazol-3-ylmethyl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.