Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: BrC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(C3CCCCC3)c3c2CCNCC3)cc1
Yield: 11.4 %

Procedure:
The title compound (15 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.40 mmol) using bromo-cyclohexane (1.5 mmol) in place of chloro-cyclobutane according to Example 238. MS (ESI): exact mass calculated for C19H24ClN3, 329.17. found, m/z 330.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.41 (m, 4H), 4.30-4.27 (m, 1H), 3.44-3.42 (m, 2H), 3.31-3.26 (m, 4H), 2.98-2.96 (m, 2H), 1.93-1.84 (m, 5H), 1.70-1.65 (m, 1H), 1.46-1.40 (m, 2H), 1.24-1.89 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH2:26][CH2:27][N:28]1[C@@H:33]([CH3:34])[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][C@H:29]1[CH3:42])=[O:24]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH2:26][CH2:27][N:28]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:42])=[O:24]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl (cis)-4-[2-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)ethyl]-3,5-dimethyl-1-piperazinecarboxylate (0.95 g) [see Preparation 8] in dichloromethane (10 ml) at 0° C. The reaction mixture was then stirred at room temperature for 1.5 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between saturated potassium carbonate solution and ethyl acetate. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The product was azeotroped several times with dichloromethane to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,6-dimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (0.65 g) as a white foam.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:8][C:7]=1[N+:26]([O-:28])=[O:27].O.[OH-].[Li+]>O1CCCC1.O>[CH2:30]([O:29][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:8][C:7]=1[N+:26]([O-:28])=[O:27])[C:3]([OH:32])=[O:2])[CH3:31]
Reactant: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1[N+](=O)[O-])C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1[N+](=O)[O-])C(=O)O
Yield: 92.9 %

Procedure:
2-Ethoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)-2-nitrophenyl]propanoic acid methyl ester (described in Example 35) (0.8 g; 1.71 mmole) was dissolved in tetrahydrofuran (8 ml). A solution of lithium hydroxide monohydrate (0.086 g; 2.05 mmole) in water (8 ml) was added under stirring. The reaction mixture was stirred at room temperature for 5 hours and then evaporated to remove tetrahydrofuran. The residue was extracted with diethyl ether, acidified to pH˜3 with hydrochloric acid (10%) and extracted with ethyl acetate. The organic phase was washed with water and brine, dried with magnesium sulfate. The solvent was removed and 0.72 g (93% yield) of 2-ethoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)-2-nitropheny]propanoic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.[NH4+].[Cl-]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:20][CH:22]3[CH2:23][O:24]3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: BrCC1CO1
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC2CO2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
Ethyl 8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.025 g, 0.097 mmol) was dissolved in anhydrous degassed THF and was cooled to −78° C. A solution of n-BuLi (0.082 mL, 1.78 M in hexanes) was added dropwise and the reaction was stirred at −78° C. for 30 min. Epibromohydrin (0.016 mL, 0.194 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After 3.5 h, epibromohydrin (0.008 mL, 0.097 mmol) was added and the reaction was stirred overnight at ambient temperature. Upon completion, saturated aqueous NH4Cl was added to quench the reaction and the mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by chromatography (SiO2, 0-50% EtOAc/Hexane) to afford the desired product (15 mg, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:32][C:31]3[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=3)[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(C(F)(F)F)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.82 g, 19.0 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (1.10 g, 28.5 mmole). After 10 min, 4-trifluoromethylbenzyl bromide (5.0 g, 20.9 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (8.73 g, 99%) as a white solid: MS (ES) m/e 465 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[C:11]([Cl:22])[C:10]=1[F:23])(C)(C)C.Cl>O1CCOCC1>[Cl:22][C:11]1[C:10]([F:23])=[C:9]([CH:14]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=1)[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1cc(CN2CCOCC2)cc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc(CN2CCOCC2)cc(Cl)c1F

Procedure:
was prepared according to Scheme C2 (step D) from (3-chloro-2-fluoro-5-morpholin-4-ylmethyl-benzyl)-carbamic acid tert-butyl ester (231 mg, 0.64 mmol) and 4N HCl in dioxane. MS (LC-MS): 259.0 [M]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][CH3:15])=[O:5].C1(=O)[NH:20]C(=O)C2=CC=CC=C12.[K].O.NN.Cl>O.C(O)(=O)C.CN(C)C=O>[NH2:20][CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][CH3:15])=[O:5]
Reactant: CCc1cccc(C)c1NC(=O)CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: NN
Agent: [K]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NC(=O)CCN

Procedure:
The 3-bromo-2'-ethyl-6'-methylpropionanilide (13.5 g, 0.0500 mole) described above, potassium phthalimide (10.2 g, 0.0551 mole), and dimethylformamide (50 ml) were stirred under reflux for two hours. A mixture of glacial acetic acid (20 ml) and water (50 ml) was added with continued stirring until the mixture reached room temperature. The solid phthalimide derivative was filtered off, washed with water, and dried. The yield: 13.8 g (82.1%), m.p.: 208°-209.5° C. This product (13.8 g, 0.041 mole) was suspended in 250 ml alcohol and an amount of 85% hydrazine hydrate (4.0 ml) was added. The mixture was refluxed with stirring for two hours. Concentrated hydrochloric acid (8 ml) was added and the stirring was continued until the mixture reached room temperature. The solid was filtered off, was washed with some 95% ethanol, and was discarded. The solvents were evaporated from the filtrate and the residue was dissolved in water, was filtered, and made basic with 7 M sodium hydroxide, and was extracted exhaustively with methylene chloride. The extracts were dried (K2CO3), were filtered, and gaseous hydrogen chloride was fed into the solution. The salt that was formed was filtered off, was washed with methylene chloride, and was dried (9.5 g), and was recrystallized from alcohol-ether. Yield of 3-amino-2'-ethyl-6'-methylpropionanilide: 7.35 g, m.p.: 215.5°-216° C. Calcd. for C12H19ClN2O: C 59.4, H 7.89, Cl 14.6, N 11.5. Found: C 59.3, H 7.80, Cl 14.6, N 11.7.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]3[S:29][CH:28]=[N:27][CH:26]=3)=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:35][CH3:36].C([O-])(=O)C.[Na+].C(OCC)(=O)C.[NH4+].[OH-]>C(OC(=O)C)(=O)C.C(OCC)C>[Br:1][C:2]1[C:3]([O:35][CH3:36])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:15]4[C:16](=[O:17])[N:18]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:19][CH2:20][O:21][CH2:22][C:23]=4[C:24]([C:25]4[S:29][CH:28]=[N:27][CH:26]=4)=[C:9]3[C:10]=2[CH:11]=1
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCOCC#Cc1cncs1)C(C)(C)C)CC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A solution of 480 mg of 11h in 7 ml of acetic anhydride and 500 mg of anhydrous sodium acetate was heated at 105° C. for 30 min. The reaction mixture was cooled and treated with 40 ml of ice-water and stirred for 1 hr at ambient temperature to break down excess anhydride. Then, 30 ml of ethyl acetate was added and the stirred mixture was treated with cold conc. aq. NH4OH, to adjust the pH of the reaction mixture to slightly basic. The materials were extracted into ethyl acetate, washed with water, dried and concentrated. The residue was passed over a short silica column, using a gradient of toluene/ethyl acetate as eluent and the purified material thus obtained was treated with diethyl ether, to give 290 mg of 11i as white crystals; Mp 219-220° C.; Rf 0.35 (toluene/ethyl acetate 1/1). MS-ESI: [M+1] 516.04, 518.05.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]([CH3:11])[CH3:10]>C1C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[S:12]([CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:14])=[O:13])[CH:2]=[CH2:3]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: C=CCNCC=C
Solvent: c1ccccc1
Product: C=CCN(CC=C)S(=O)(=O)CC(C)C

Procedure:
A solution was formed containing 19.4 g. of diallylamine in 100 ml. of benzene. Then, 15.7 g. of isobutylsulfonyl chloride was added at such a rate that the temperature did not exceed 45° C. The mixture was stirred and refluxed for ten minutes, cooled, washed with 100 ml. of dilute hydrochloric acid and then with H2O. It was then dried over magnesium sulfate, filtered and evaporated to give 20.1 g. (02% of theory) of the product, a liquid, nD30 = 1.4697.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6][C:5]2=O.[OH-].[Na+].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2[nH]ccc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C

Procedure:
6-Methyl-(1H)-quinolin-4-one (1.57 g, 9.7 mmol) in 20 mL phosphorus oxychloride is heated to 110° C. for 4 hours. The mixture is cooled to room temperature then diluted with ice water (˜200 mL) and the pH is adjusted to ca. 10 by the slow addition of 10 N NaOH. The aqueous solution is extracted with methylene chloride (4×250 mL) and the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue is filtered through silica gel with 33% EtOAc/hexanes to give the product (1.05 g, 5.9 mmol) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:35]([Cl:37])=[O:36])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-2-{4-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-propan-2-ol was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=[C:5]2[CH:16]([CH3:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC>C1COCC1>[CH:16]([C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([C:24](=[O:26])[CH3:25])[CH:3]=2)[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=1)([CH3:18])[CH3:17]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc2c(cc1Br)C(C(C)C)=CC(C)(C)O2
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure H, a solution of 6-bromo-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chroman-4-one (Compound 14, 290 mg, 0.94 mmol) in THF was treated with tributyl(1-ethoxyvinyl)tin (0.63 mL, 1.88 mmol) to give the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[CH:19][N:18]=[C:17]4[C:21]4[CH2:22][CH2:23][O:24][CH2:25][CH:26]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:27])[C:8](=[O:28])[C@H:7]2[CH2:29][CH3:30])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:27])[C:8](=[O:28])[C@H:7]2[CH2:29][CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3C3=CCOCC3)nc2N1C1CCCC1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3C3CCOCC3)nc2N1C1CCCC1

Procedure:
(R)-8-cyclopentyl-2-(2-(3,6-dihydro-2H-pyran-4-yl)-1H-imidazol-1-yl)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 84, 34 mg) in 5 mL of MeOH, Pd/C (20 mg) was added. This reaction mixture was placed under a hydrogen balloon until all the starting material was consumed. The resulting mixture was filtered through a plug of Celite, and the plug was washed several times with EtOAc. The mixture was concentrated under reduced pressure and further purified by preparative HPLC. LCMS: 411.2 m/z (M+H)+; ret. Time: 6.45 min (Analytical Method C).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH2:5][CH2:6][OH:7].[OH-].[Na+:15]>O>[OH:1][CH2:2][CH2:3][N:4]([C:8]([CH3:13])([CH3:12])[C:9]([O-:11])=[O:10])[CH2:5][CH2:6][OH:7].[Na+:15]
Reactant: CC(C)(C(=O)O)N(CCO)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C(=O)[O-])N(CCO)CCO

Procedure:
2-[N,N-bis-(2-hydroxyethyl)amino]-2-methylpropanoic acid (423.46 grams, 2.21 moles) (this material is about 99% pure; it contains 1% H2O) is added with stirring to a cooled solution of pure sodium hydroxide (88.57 grams, 2.21 moles) in pyrogen-free distilled water (400 ml.). The mixture is stirred until solution is effected. After reaching room temperature, the solution is stirred while enough pyrogen-free distilled water is added to make the total volume 1,000 ml. The solution is sterilized by filtration. This solution contains 47.4% by weight of, or is 2.21 molar in, sodium 2-[N,N-bis-(2-hydroxyethyl)-amino]-2-methylpropanoate.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]([F:22])([F:21])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19].[I:23]I>C1CCCCC1.C1COCC1>[I:23][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]([F:21])([F:22])[F:6])[C:10]=1[NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19]
Reactant: II
Reactant: CCOC(=O)Nc1ccccc1OC(F)(F)F
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(I)cccc1OC(F)(F)F
Reaction time: 1 h
Yield: 73 %

Procedure:
A 1.4 M solution of sec-butyllithium in cyclohexane (3.0 mL) was added drop-wise to a solution of ethyl N-[2-(trifluoromethoxy)phenyl]carbamate (0.5000 g, 0.002006 mol) in THF (9 mL) at −70° C. After stirring for 1 hour a solution of iodine (0.51 g, 0.002 mol) in THF (1.0 mL) was added drop-wise at −70° C. Stirring was continued for another 1 hour then the mixture was quenched with saturated ammonium chloride solution. Water (50 mL) was added and the mixture extracted with diethyl ether (3×40 mL). The combined organic phases was washed with 40% sodium meta-bisulfite solution, water and brine, then dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 73% yield. 1H NMR (400 MHz, CDCl3): δ 1.29-1.36 (m, 3H), 4.21-4.28 (m, 2H), 6.21 (br, 1H), 7.05 (t, J=8.0 Hz, 1H), 7.30 (m, 1H) and 7.80 (dd, J=6.8, 1.2 Hz, 1H). MS (ES+): m/z 375.78 [MH+].
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>ClCCl>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
Add sodium borohydride (0.82 mol, 31.3 g) in portions to a solution of 1-(tert-butoxycarbonyl)-4-piperidone (0.74 mol, 150 g) and triethylamine (1.5 mol, 151.6 g) in dichloromethane (1 L) at 0° C. Upon complete addition, warm the reaction mixture to room temperature and stir for 4 h. Quench the reaction mixture with saturated ammonium chloride solution and remove the ethanol under reduced pressure. Dissolve the residue in water and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (150 g, 99%) as a viscous solid. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.53 (d, 2H), 1.83-1.87 (m, 2H), 3.02 (dt, 2H), 3.8-3.85 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.I[CH2:13][CH3:14].[BH4-].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH3:14])[CH2:7]2
Reactant: Nc1cccc2cnccc12
Reactant: CCI
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CCc2c(N)cccc2C1

Procedure:
The title compound was prepared by treatment of 5-aminoisoquinoline with iodoethane followed by reduction with sodium borohydride using procedures analogous to those described in Preparation 1 and Preparation 2.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25](=[O:30])[CH2:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from [4-(4-chloro-phenoxy)-piperidin-1-yl]-oxo-acetic acid and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 198-200° C. (diethyl ether)
Reaction SMILES: [H-].[Na+].[NH:3]1[C:10]2[N:6]([N:7]=[CH:8][CH:9]=2)[CH:5]=[CH:4]1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(OCC)(=O)C>CN(C)C=O.O>[CH2:16]([O:15][C:13]([CH2:12][N:3]1[C:10]2[N:6]([N:7]=[CH:8][CH:9]=2)[CH:5]=[CH:4]1)=[O:14])[CH3:17]
Reactant: c1cc2[nH]ccn2n1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 62% sodium hydride (7.23 g) in N,N-dimethylformamide (70 ml) was added 1H-imidazo[1,2-b]-pyrazole (20 g) by portions under ice-cooling. A solution of ethyl bromoacetate (20.7 ml) in N,N-dimethylformamide (50 ml) was added thereto at the same condition. The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a mixture of ethyl acetate (1 l) and water (500 ml). The separated organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated in vacuo to give 1-ethoxycarbonylmethyl-1H-imidazo[1,2-b]pyrazole (25 g).
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1OCCC1=CO
Reactant: NCc1ccccc1
Agent: [Na]
Product: O=C1OCCC1=CNCc1ccccc1

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and benzylamine (55 mmol) and using the abovementioned method A1, 3-benzylaminomethylenedihydrofuran-2-one is produced (7.50 g, efficiency: 70%) in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1ccc(N)cc1Cl
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of methyl 2-(2-chloro-4-nitrophenyl)acetate (step 3, 3.6 g, 15.6 mmol) in ethanol/water (4/1) were added Fe (4.4 g, 78.0 mmol) and NH4Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 h under reflux temperature. The solvent was removed and the residue was diluted with CH2Cl2.The mixture was washed with brine, dried (MgSO4) and concentrated to give 2.59 g (83%) of title compound as orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)Cl

Procedure:
A solution of 2-methylbenzoic acid (10 g, 1.00 equiv) in thionyl chloride (50 mL) was refluxed overnight at 80° C. in an oil bath. The reaction mixture was concentrated under vacuum to afford 2-methylbenzoyl chloride (crude) as a colorless oil.