Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[C:35](=O)([O-:37])[OH:36].[Na+:39].C(=O)=O>CC(C)=O>[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH:34][C:35]([O-:37])=[O:36])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[Na+:39]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Reactant: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NC(=O)[O-])n1
Reaction time: 5 h
Yield: 38.4 %

Procedure:
To a solution of 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (1.15 g) in 50% aqueous acetone (9.2 ml) was added sodium hydrogencarbonate (193 mg) and dry ice (4.4 g) at room temperature. The mixture was stirred in a sealed tube for 5 hours. Acetone was removed under reduced pressure. The residual solution was chromatographed on non-ionic adsorption resin "Diaion HP-20" (Trademark, maker: Mitsubishi Chemical Industries) eluting with water. The desired fractions were collected and lyophilized to give sodium 7-[2-allyloxyimino-2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (500 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1.Cl.[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([OH:36])([CH3:35])[CH3:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[C:33]([OH:36])([CH3:35])[CH3:34])[NH:12][C:11]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[N:10]1
Reactant: CC(C)(O)[C@@H]1CCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCC[C@H]2C(C)(C)O)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 25.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (S)-2-(pyrrolidin-2-yl)propan-2-ol hydrochloride (0.25 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.21 g, 26%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1ccccn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccccn4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Yield: 29 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the desired product in 29% yield;
Reaction SMILES: [C:1]([CH2:14][CH2:15][C:16]#[N:17])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]>C1COCC1>[F:2][C:1]([F:3])([C:4]([F:5])([F:6])[C:7]([F:8])([F:9])[C:10]([F:11])([F:12])[F:13])[CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: N#CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Product: NCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 110 °C
Reaction time: 16 h
Yield: 13.1 %

Procedure:
A 210-ml shaker tube was charged with 30 g of C4F9CH2CH2CN, 4.0 g of PtB on activated carbon (2%) and 30 ml THF. The vessel was closed, cooled, evacuated and pressured with hydrogen to 3.5 MPa. The vessel was heated to 110° C. and hydrogen pressure was adjusted to 10.3 MPa. The mixture was shaken for 16 h. The vessel was cooled and the gas was vented slowly. The contents were filtered and the filtrate was distilled to remove THF. The residue was distilled at reduced pressure to give 4,4,5,5,6,6,7,7,7-nonafluoroheptylamine (4.0 g, 13%, b.p. 94-97° C./24 kPa absolute) and di(4,4,5,5,6,6,7,7,7-nonailuoroheptyl)amine (20.5 g, 69%, b.p. 105-108° C./270 Pa absolute). The distillation residue (0.2 g) was mainly (C4F9CH2CH2CH2)3N.
Reaction SMILES: [OH-].[Li+].C([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])(=O)C.O.Cl>C1COCC1>[OH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(OC(C)=O)c(CC=C(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Yield: 75.4 %

Procedure:
Lithium hydroxide (85 mg, 2.02 mmol) was added to a mixture of methyl ester 7 (106 mg, 0.405 mmol) in 0.5 mL of a 3/1/1 THF/eOH/H2O solution. The reaction mixture was stirred at reflux for 14 hours, cooled to room temperature, and diluted with THF (1 mL). The solution was acidified the solution to pH=3 by the dropwise addition of 6 M HCl. The layers were separated and the organic phase was dried (Na2SO4), filtered, and concentrated to afford acid 8 (63 mg, 75%) as a red oil that was suitable for use without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:9]=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 0.0508 mol) in DMF (40 mL) was cooled under nitrogen to 0° C. Sodium hydride (3.0 g, 0.075 mol) was added portionwise. The reaction was stirred for 1 hour. To this mixture, [2-(trimethylsilyl)ethoxy]methyl chloride (10.8 mL, 0.061 mol) was added slowly. After being stirred at 0° C. for 1 hour, the reaction was quenched with water and extracted with EtOAc twice. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-25% EtOAc/hexanes to afford 15.7 g (94.5%) of the desired product as a yellowish oil. LC/MS found: 327.1, 329.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:13])[F:14])=[CH:10][N:9]=1)(=[O:25])=[O:24]
Reactant: OCc1ccc(OCC(F)(F)F)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(OCC(F)(F)F)cn1
Yield: 67.5 %

Procedure:
To a dichloromethane solution (2.8 mL) of [5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methanol (138 mg, 0.67 mmol), triethylamine (468 μL, 3.33 mmol) and methanesulfonyl chloride (77.4 μL, 1.00 mmol) were added at 0° C. and the resultant solution was stirred for 30 minutes. After completion of the reaction, the reaction solution was washed with saturated ammonium chloride aqueous solution and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product (129 mg) of the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(S)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To an ambient temperature solution of 4-Mercaptophenylacetic acid (5.0 g, 29.72 mmol) in MeOH (250 mL) is added sulfuric acid (1.25 mL). The reaction mixture is stirred at room temperature overnight. The reaction is concentrated and the residue is partitioned between Et2O and water. The aqueous layer is extracted with Et2O and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 30% EtOAC/Hex) to yield the title compound (3.69 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H, J=7.9 Hz), 7.12 (d, 2H, J=8.4 Hz), 3.66 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[N+:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[C:16]=1Cl)([O-:14])=[O:13].Cl>CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:16]2[C:17]([N+:25]([O-:27])=[O:26])=[CH:18][C:19]([C:21]([F:24])([F:22])[F:23])=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: Nc1ncc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Nc1ncc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
In 20 ml. of dimethylformamide, 1.65 g. of 2-amino-3,5-dichloropyridine was dissolved and 1.0 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, 2.7 g. of 2,6-dinitro-4-trifluoromethylchlorobenzene was added at 30° C. during 5 minutes and the reaction was continued for about 3 hours. The reaction mixture was acidified with conc. HCl and the product was extracted with methylenechloride. The extracted layer was washed with water and dehydrated. The solvent was distilled off and the product was separated by a silica gel column with an eluent of toluene and the solvent was distilled off to obtain 2.8 g. of the object compound having the melting point of 85° to 87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](OCC)[N:8]([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19].[O-]CC.[Na+].[Na]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:21][CH:18]([CH3:20])[CH3:19])[N:8]([CH3:12])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: CCOC1=Nc2ccc(Cl)cc2S(=O)(=O)N1C
Reactant: CC(C)N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)NC1=Nc2ccc(Cl)cc2S(=O)(=O)N1C

Procedure:
A mixture of crude 7-chloro-3-ethoxy-2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (0.45 g) and isopropylamine (4 ml) in an ethanolic sodium ethoxide solution, prepared by dissolving 0.4 g of sodium in 10 ml of ethanol, was refluxed for 3 hours and then neutralized with 4M acetic acid. The mixture was evaporated to dryness and partitioned between 25 ml of water and 25 ml of dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column with a 7:3 mixture of n-heptane and ethyl acetate as solvent to give the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11][OH:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:11][O:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: N#CC(=NO)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A stirred solution of 2-(4-fluorophenyl)-2-hydroxyiminoacetonitrile (42.8 g, 0.26 mole) in 200 ml of pyridine was cooled to 0° C., and p-toluenesulfonyl chloride (76.0 g, 0.39 mole) was added portionwise. Upon complete addition, the reaction mixture was stirred at 0°-5° C. for one hour and then stored in a refrigerator for 16 hours. The resultant slurry was poured into a mixture of ice and water and stirred for 30 minutes. The mixture was then filtered and the white filter cake dried under vacuum without heat to give 2-(4-fluorophenyl)-2-(4-methylphenylsulfonyloxy)iminoacetonitrile (77.3 g, mp 129°-140° C.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1.[CH2:19]([NH2:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:19]([NH:31][C:17]([CH:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1CC(CSc2nc3ccccc3s2)C(=O)O1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC(=O)C(CSc1nc2ccccc2s1)CC(=O)O

Procedure:
A mixture of 6.5 parts of 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylic anhydride and 4.3 parts of dodecylamine is heated at 55° during 3 hours to give a mixture of the two isomeric mono-dodecylamides as a yellow oil.
Reaction SMILES: [Si](OCC1SC(C(CN2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)C2=O)C(OC)=O)=CC=1)(C(C)(C)C)(C)C.[Li+].[OH-:33].O>C1COCC1.O>[C:29]([OH:30])(=[O:33])[C:28]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To methyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-3-(1,3-dioxoisoindolin-2-yl)propanoate (E233) in THF/H2O was added LiOH*H2O, and the solution was stirred for 1.5 h or until complete conversion to product was visible by LC-MS. The solution was then poured into EtOAc/NH4Cl(sat)/1 N HCl (3:1) and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, evaporated, and dried to give crude 2-(2-(5-(tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-2-carboxyethylcarbamoyl)benzoic acid (E234).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH:38]1([CH2:37][NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH2:39][CH2:40]1
Reactant: Nc1cccc(S(=O)(=O)NCC2CC2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCC2CC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-cyclopropylmethyl-benzenesulfonamide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 564.2 [(M−H)−]; mp 238° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH:10]([C:13]1[S:17][CH:16]=[C:15]([C:18]([N:20]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][CH2:22][CH2:21]2)=[O:19])[CH:14]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>C(#N)C>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][C:24]2([O:23][CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:14]=[C:13]([CH:10]([CH3:11])[CH3:12])[S:17][CH:16]=3)=[O:19])[CH2:25]2)[CH2:26][CH2:27]1
Reactant: CC(C)c1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(CCCCCCCO)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 7-bromo-1-heptanol (380 mg) in acetonitrile (3.9 mL) was added to a solution of (5-isopropylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (Example 275, step i) (400 mg) and triethylamine (0.361 mL) in acetonitrile (8.6 mL). The resulting mixture was stirred at 60° C. for 16 hours. The solvent was removed under vacuum and the residue taken up in DCM (25 mL) and washed with brine (25 mL) and water (20 mL), then dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 10% methanol in DCM to afford the subtitled compound as a pale brown solid. Yield 0.305 g.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:25][CH:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[NH:23][N:22]=2)=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:23]2[CH:24]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[CH2:25][C:21]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)=[N:22]2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Reactant: Clc1ccc(C2=NNC(c3ccc(Cl)cc3)C2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)F)cc1)N1N=C(c2ccc(Cl)cc2)CC1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
5.55 g (0.03 mol) of 4-difluoromethoxy-phenyl isocyanate in 20 ml of toluene were added, at 50° C., to a solution of 8.74 g (0.03 mol) of 3-(4-chlorophenyl)-5-(4-chlorophenyl)-2-pyrazoline in 100 ml of toluene and the batch was stirred for 2 hours at 80° C. After it had cooled, the product which had precipitated was isolated by filtration. 5 g (35% of theory) of 1-(4-difluoromethoxyphenylcarbamoyl)-3-(4-chlorophenyl)-5-(4-chlorophenyl)-2-pyrazoline of melting point 174° C. were obtained.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:11]2>>[CH3:22][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])[CH:9]=2)[CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CC(C)=CCBr
Product: CC(C)=CCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-bromo-3-methyl-2-butene and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 97°-100° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:30])[C:3]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[S:7][C:6]1([CH2:24][CH2:25][CH2:26][N:27]=[N+]=[N-])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].Cl.N#N>CO.[Pd]>[NH2:1][CH:2]([CH3:30])[C:3]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[S:7][C:6]1([CH2:24][CH2:25][CH2:26][NH2:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:4]
Reactant: CC(N)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CO
Product: CC(N)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Reaction time: 40 h
Yield: 87.4 %

Procedure:
2-Amino-1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)propan-1-one (50 mg, 0.116 mmol) was dissolved in 5.0 mL of MeOH. HCl (0.46 ml, 0.464 mmol) was added followed by evacuation/re-vacuation with N2. Pd/C (12 mg, 0.011 mmol) was then added followed by H2 balloon. Following 40 hours at 23° C., the reaction was concentrated in vacuo, affording the product (41 mg, 87%) as a cream/yellow colored foam. MS ESI (+) m/z 405 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ7.68 (m, 1H), 7.53 (m, 2H), 7.42 (t, 2H, J=9 Hz), 7.34 (m, 3H), 4.92 (m, 1H), 3.22 (m, 2H), 3.17 (m, 4H), 2.65 (m, 2H), 2.20 (m, 1H), 1.99 (m, 1H), 1.72 (d, 1.5H, J=8 Hz), 1.66 d, 1.5H, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]3=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=[CH:21][N:7]3[N:6]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:22]1([C:19]2[CH:20]=[CH:21][N:7]3[C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:5]([C:2]2([NH:1][C:34](=[O:36])[CH3:35])[CH2:3][CH2:4]2)=[N:6]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a stirred solution of 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.168 mmol)) in DCM (15 mL) was added pyridine (0.0200 mL, 0.253 mmol) followed by acetyl chloride (0.0140 mL, 0.202 mmol) and the reaction mixture stirred at RT for 2 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-111 as described in general methods) to give N-(1-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)acetamide (25.0 mg, 37.3%) as white solid. LCMS Condition B-34: retention time 2.14 min, [M+1]=399.0. HPLC Condition B-31: retention time 6.09 min, Purity 99.83%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-1.01 (m, 2H), 1.35-1.41 (m, 2H), 1.85 (s, 3H), 4.68 (d, J=4.8 Hz, 2H), 6.68 (d, J=2.7 Hz, 1H), 6.99 (t, J=4.9 Hz, 1H), 7.27 (dd, J=6.5 Hz, J=4.9 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.40-7.48 (m, 1H), 7.48-7.57 (m, 4H), 7.67 (d, J=2.7 Hz, 1H), 7.76 (td, J=7.7 Hz, J=1.7 Hz, 1H), 8.37-8.41 (m, 1H), 8.44 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH2:26][N:27]=[C:28]=[O:29]>C1(C)C=CC=CC=1>[Cl:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:21][CH:22]=1
Reactant: Cc1cccc(N2CCN(CCc3ccc(N)cc3)CC2)c1
Reactant: O=C=NCCCCl
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3ccc(NC(=O)NCCCCl)cc3)CC2)c1

Procedure:
11.3 gm (38.5 millimols) of N-(p-amino-phenethyl)-N'-(m-tolyl)-piperazine, 4.6 gm (38.5 millimols) of 3-chloropropyl-isocyanate and 120 ml of toluene were admixed with each other, accompanied by gentle agitation, and the mixture was allowed to react for two hours and was then vacuum-filtered, yielding as the filter cake 90% of theory of N-[p-(3-chloropropyl-ureido)-phenethyl]-N'-(m-tolyl)-piperazine, m.p. 168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 3-chlorobenzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 hours. After cooling to 4° C., the resulting precipitate was collected and dried to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. (Yield 25.2 g, 95%).