Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:16][CH3:17])[O:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:6]2[CH2:5][CH:4]=1.C(N(CC)CC)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].Cl>CN(C)C=O>[Si:25]([O:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:16][CH3:17])[O:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:6]2[CH2:5][CH:4]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO)=CC[C@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO[Si](C)(C)C(C)(C)C)=CC[C@H]12
Reaction time: 1 h
Yield: 93.9 %

Procedure:
3 g (12.5 mmol) of methyl (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran4-carboxylate was dissoved in 50 ml of dimethylformamide and 1.9 ml (13.8 mmol) of triethylamine was added thereto under nitrogen atmosphere. The reaction solution was stirred for one hour and then 2.07 g (13.8 mmol) of t-butyldimethylsilylchloride dissolved in 10 ml of dimethylformamide was added dropwise thereto. After stirring for 3 hours, 1N-aqueous hydrochloric acid solution was added in order to stop the reaction. Organic layer was extracted by the addition of diethylether and then it was washed with saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 4.16 g (Yield 94%) of methyl (1R,4aS,7aS)-7-(t-butyldimethylsilyloxymethyl)-1 -methoxy-1,4a,5,7a-tetrahydrocyclo penta[c]pyran-4-carboxylate as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:3]2[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][CH2:8][C:2]2=[O:1])=[CH:23][CH:22]=1
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CN=C(c3ccccc3)c3ccccc32)cc1

Procedure:
A mixture of 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine (13.43 g, 57 mmmol, prepared as described by Mark G. Bock et al in Journal of Organic Chemistry, Vol. 52, pp. 3232-3239, year 1987), 4-methoxybenzyl chloride (12.6 mL, 62.5 mmol) and potassium carbonate (15.7 g, 114 mmol) in N,N-dimethylformamide (130 mL) was heated at 60° C. overnight under an atmosphere of argon. The resultant slurry was concentrated and the residue was treated with ethyl acetate and water. The organic extract was separated, washed twice with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuo. The residue was subjected to column chromatography on silica gel eluting with 1:1 ethyl acetate and hexane. Collection and concentration of appropriate fractions provided 2,3-dihydro-1-[4-methoxybenzyl]-2-oxo-5-phenyl-1H-1,4-benzodiazepine.
Reaction SMILES: Br[C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:30][NH2:31].CO.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu]I>[CH3:30][NH:31][C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(OC2c3cccc(Br)c3CCn3cc(-c4ccccc4)nc32)CC1
Reactant: CN
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1cccc2c1CCn1cc(-c3ccccc3)nc1C2OC1CCN(C)CC1
Temperature: 100 °C
Reaction time: 36 h

Procedure:
To a solution of 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (276 mg, 0, 55 mmole) in dimethylformamide (5 mL) in a screw-capped vial are added a 3M solution of methylamine in methanol (2.8 mL, 5.5 mmoles), copper(I) iodide (100 mg, 0, 52 mmole) and cesium carbonate (250 mg, 0.77 mmole). The vial is evacuated and filled with argon. The reaction mixture is stirred at 100° C. for 36 hours. Water and ammonia are added to the reaction mixture, and the aqueous phase is extracted three times with dichloromethane. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 11% (B) to 21% (B) in 10 minutes) to afford methyl-[4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-8-yl]-amine melting at 189° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:20])=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1>C1COCC1>[N+:37](=[C:14]1[C:13](=[O:20])[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[O:16][C:15]1=[O:19])=[N-:38]
Reactant: O=c1cc(O)c2ccc(OCc3ccccc3)cc2o1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)Oc2cc(OCc3ccccc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of 7-benzyloxy -4-hydroxy coumarin (2.5 g, 9.3 mmol; prepared in accordance with Example 5) in anhydrous THF (40 mL) was mixed with triethylamine (0.9 g, 9 mmol) taken in a 100 mL 3-neck round-bottom flask under an atmosphere of N2. A solution of p-toluenesulfonyl azide (2.8 g, 14 mmol) in dry THF (20 mL) was added dropwise through an addition funnel. The mixture was stirred at room temperature for 3 hrs. The color of the solution turned orange. The solvent was rotary evaporated and the product was taken in CH2Cl2 and washed with water (3 times). Petroleum ether (twice the volume) was added to the solution and the solid precipitate was filtered with a flit and dried at 45° C. The product was recrystallized using CH2Cl2 ; yield 90%. The product was characterized by NMR: 13C NMR (100 MHz, CD2 Cl2): 173.3, 165.4, 158.7, 156.0, 136.0, 129.1, 128.8, 128.0, 127.6, 113.9, 113.0, 103.0, 75.7, 71.2; DSC--m. pt. 191° C. followed by decomposition; IR (KBr): 2182, 2154, 1717, 1647, 1605 cm-1 ; MS(APCI): (M+H), 295 (base peak).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([C:26]3[C:27]([CH3:36])=[N:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:25])=[CH:18][C:17]=2[F:37])(=O)=O)=CC=1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:64].[K+]>CC#N.O>[F:37][C:17]1[CH:18]=[C:19]([CH2:22][NH:23][C:24]([C:26]2[C:27]([CH3:36])=[N:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][N:30]=3)=[O:25])[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][CH2:13][CH2:12][F:64]
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2ccc(CNC(=O)c3cc4cccnc4nc3C)cc2F)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nc2ncccc2cc1C(=O)NCc1ccc(COCCF)c(F)c1
Temperature: 25 °C

Procedure:
A flask with a solution of 19 mg 2-[[2-fluoro-4-[[(2-methyl-1,8-naphthyridine-3-carbonyl)amino]methyl]phenyl]methoxy]ethyl 4-methylbenzenesulfonate (0.036 mmol), 26 mg Kryptofix 222 (4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane) (0.069 mmol) and 4 mg KF (0.069 mmol) in 1.0 ml dry MeCN was added to a preheated oil bath and heated at 90 C for 30 min. The reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and concentrated. Flash chromatography gave 9.6 mg (72%).
Reaction SMILES: Cl[C:2]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[Cl:17][C:12]1[C:11](/[C:2](/[NH:27][CH:25]([C:22]2[CH:23]=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH3:26])=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CC(N)c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C#N)=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C(C#N)=C(\NC(C)c1ccc(Cl)nc1)c1cccnc1Cl
Yield: 73 %

Procedure:
To a solution of ethyl 3-chlor-3-(2-chloropyridin-3-yl)-2-cyanoacrylate (0.150 g, 0.55 mmol, 1 eq.) in 3 ml of acetonitrile was added 1-(6-chloropyridin-3-yl)ethanamine (0.103 g, 0.66 mmol, 1.2 eq.) followed by triethylamine (TEA) (0.167 g, 1.66 mmol, 3 eq.). The reaction was microwaved (130° C., 600 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was subjected to column chromatography to give ethyl (2Z)-3-(2-chloropyridin-3-yl)-3-{[1-(6-chloropyridin-3-yl)ethyl]amino}-2-cyanoacrylate (0.157 g, 68% yield) as a mixture of 2 atropoisomers.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a suspension of 25.6 g (100 mmol) of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid in 75 ml of dichloromethane was added 14.0 g (110 mmol) of oxalyl chloride. This mixture was treated with four drops of dry N,N-dimethylformamide, and the rapidly bubbling solution was stirred overnight at room temperature. The mixture was concentrated to give 27.0 g of the title compound which was used without purification in the next step.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])O[C:3]1=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:3]1=[O:4]
Reactant: CC1CC(=O)OC1=O
Reactant: Nc1ccncc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1CC(=O)N(c2ccncc2)C1=O
Reaction time: 3.5 h

Procedure:
The starting material is prepared as follows: The mixture of 28.5 g of 2-methylsuccinic anhydride, 23.5 g of 4-aminopyridine and 350 ml of xylene is refluxed on a water separator while stirring for 3.5 hours. The hot solution is decanted from some gummy residue, cooled, filtered, the residue suspended in 100 ml of boiling isopropanol and filtered off again, to yield the 3-methyl-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 119°-120°.
Reaction SMILES: Cl.C(N/[C:5](=[C:8]1/[CH2:9][CH2:10][C@@H:11]2[C@:25]/1([CH3:26])[CH2:24][CH2:23][C@@:22]1([OH:27])[C@H:12]2[CH2:13][CH:14]=[C:15]2[C@:20]1([CH3:21])[CH2:19][CH2:18][C:17]([O:28]C)=[CH:16]2)/[CH2:6][OH:7])=O.C[OH:31]>>[OH:27][C@:22]12[CH2:23][CH2:24][C@@:25]3([CH3:26])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C:5](=[O:31])[CH2:6][OH:7])[C@@H:12]1[CH2:13][CH2:14][C:15]1[C@:20]2([CH3:21])[CH2:19][CH2:18][C:17](=[O:28])[CH:16]=1
Reactant: COC1=CC2=CC[C@H]3[C@@H]4CC/C(=C(\CO)NC=O)[C@@]4(C)CC[C@]3(O)[C@@]2(C)CC1
Reactant: CO
Agent: Cl
Product: C[C@]12CC[C@@]3(O)[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous 5N hydrochloric acid (1 ml) was added to a stirred solution of (20Z)-20-formamido-3-methoxypregna-3,5,17(20)-triene-9α,21-diol (70 mg) in methanol (4 ml). The reaction mixture was stirred at room temperature for 1 hour, then extracted with ethyl acetate. The organic extract was washed with an aqueous sodium bicarbonate solution, twice with water, dried and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])(=O)=O)=CC=1.[CH3:19][C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][N:25]1[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C@H:20]1[CH3:19])[CH3:17]
Reactant: CCOCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCCCCN1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 3 g of 4-ethoxybutyl p-toluenesulfonate, 2.65 g of tert-butyl (3R)-3-methylpiperazine-1-carboxylate, 3.07 mL of triethylamine, and 30 mL of acetonitrile was stirred at 90° C. for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 3.1 g of tert-butyl (3R)-4-(4-ethoxybutyl)-3-methylpiperazine-1-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([CH2:11][CH2:12][CH2:13][CH3:14])=[C:6](Cl)[N:5]=1)(=[O:3])[NH2:2].C(C1C=C(Cl)C(CCCC)=C(N)N=1)(=O)N.[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: CCCCc1c(N)cc(C(N)=O)nc1Cl
Agent: [Pd]
Agent: CCCCc1c(Cl)cc(C(N)=O)nc1N
Solvent: CO
Product: CCCCc1cnc(C(N)=O)cc1N

Procedure:
11.4 g (0.05 mol) of the isomer mixture of 2-carbamoyl-4-amino-5-n-butyl-6-chloro-pyridine and 2-carbamoyl-4-chloro-5-n-butyl-6-amino-pyridine, dissolved in 120 ml of pure methanol, are hydrogenated in the presence of 1.5 g of palladium on charcoal. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is rendered alkaline with 2 N sodium carbonate solution and extracted with ether. The crystalline product which is soluble in neither sodium carbonate solution nor in ether is filtered off and rinsed with water. The white crystals are dried for 20 hours at 70° in a high vacuum. 2-Carbamoyl-4-amino-5-n-butyl-pyridine of the formula ##STR33## and of melting point 186°-190° is thus obtained.
Reaction SMILES: [Na].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.Cl[CH:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C.C(OCC)C>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:11]([O:8][C:7]2[CH:2]=[CH:3][C:4]([CH3:9])=[CH:5][CH:6]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][CH:3]=1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: Cc1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(Oc1ccc(C)cc1)Oc1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Sodium (5.7 g) is dissolved in ethanol (160 cc), and a solution of para-cresol (27 g) in ethanol (20 cc) is added. The mixture is stirred for 1 hour at 20° C. and ethyl dichloroacetate (20 g) in solution in ethanol (20 cc) is then added. The mixture is heated under reflux for 20 hours and then allowed to cool. The white precipitate obtained is filtered off and the filtrate is concentrated to dryness under reduced pressure (20 mmHg) at 40° C. The oil thus obtained is taken up in diethyl ether (300 cc) and washed twice with N sodium hydroxide solution (100 cc each time) and twice with distilled water (100 cc each time). The ethereal phase is then dried over anhydrous sodium sulphate, filtered, and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methylphenoxy)acetate (29 g) is thus obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:33].[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of (R)-tert-butyl 5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (30 mg, 0.066 mmol) in DCM was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at about room temperature overnight. The reaction was concentrated and triturated with ether (×2) to yield (R)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]dihydrochloride (21 mg, 73%). LCMS (APCI+) m/z 355, 357 [M+H]+; Rt=2.09 min.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[CH3:17]N(C)C=O>O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:17])[N:14]=2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2nnn[nH]2)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2nnn(C)n2)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-4-methoxybenzonitrile (9 g, 42 mmol), sodium azide (3.03 g, 46.7 mmol) and ammonium chloride (2.5 g, 46.7 mmol) in N,N-dimethylforlmamide (50 ml) was heated at 90° C. for 18 hours. The reaction was cooled, poured onto ice (200 ml) and acidified with 1N HCl to pH1. The resultant solid was filtered, dried and recrystallized from ethanol/water to give 2-bromo-4-(tetrazol-5-yl)anisole (9.2 g). 1H NMR 360 MHz, DMSO-d6) δ 3.95 (3H, s), 7.35 (1H, d, J=8.6 Hz), 8.05 (1H, d, =8.6 Hz), 8.23 (1H, s). To a suspension of sodium hydride (60% dispersed, 1.5 g, 37 mmol) in N,N-dimethylformamide was added the foregoing anisole (5 g, 32.5 mmol) and the reaction stirred at room temperature for 2 hours. The reaction was diluted with water (70 ml) and the resultant solid filtered, dried and chromatographed on silica eluting with 60% ethyl acetate/hexane to give 2-bromo-4-(2-methyltetrazol-5-yl)anisole (3.2 g), 1H NMR (360 MHz, CDCl3) δ 3.97 (3H, s), 4.39 (3H, s), 7.00 (1H, d, J=12.4 Hz), 8.07 (1H, dd, J=12.4 and 3.0 Hz), 8.34 (1H, d, J=3.0 Hz); and 2-bromo-4-(1-methyltetrazol-5-yl)anisole (0.8 g), 1H NMR (360 MHz, CDCl3) δ 3.94 (3H, s), 4.13 (3H, s), 7.01 (1H, d, J=8.6 Hz), 7.66 (1H, dd, J=8.6 and 2.2 Hz), 7.90 (1H, d, J=2.2 Hz).
Reaction SMILES: COC(=O)C1C=C(O)C=C(OCC=C)C=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.[CH3:31][O:32][C:33](=[O:47])[C:34]1[CH:39]=[C:38]([O:40][CH2:41][CH:42]=[C:43]([CH3:45])[CH3:44])[CH:37]=[C:36]([OH:46])[CH:35]=1>>[CH3:31][O:32][C:33](=[O:47])[C:34]1[CH:39]=[C:38]([O:40][CH2:41][CH:42]=[C:43]([CH3:44])[CH3:45])[CH:37]=[C:36]([O:46][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[Cl:22])[CH:35]=1
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1cc(O)cc(OCC=C(C)C)c1
Agent: C=CCOc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(OCC=C(C)C)cc(OCc2ccccc2Cl)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from potassium carbonate (1.25 g, 9.06 mmol), 2-chloro benzyl bromide (0.59 mL, 4.53 mmol), and 3-hydroxy-5-(3-methyl-but-2-enyloxy)-benzoic acid methyl ester (374a) (1.07 g, 4.53 mmol). Purification by flash column chromatography eluting with 5% EtOAc in hexanes gave a colorless oil (1.60 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ 7.51-7.61 (m, 1 H) 7.37-7.45 (m, 1 H) 7.30 (dd, J=3.92, 2.40 Hz, 2 H) 7.27-7.29 (m, 1 H) 7.24 (dd, J=2.27, 1.26 Hz, 1 H) 6.76 (t, J=2.40 Hz, 1 H) 5.49 (tt, J=6.82, 1.39 Hz, 1 H) 5.15-5.23 (m, 3 H) 4.54 (d, J=6.82 Hz, 2 H) 3.92 (s, 3H) 1.81 (s, 3 H) 1.73-1.79 (m, 3 H); LCMS for C20H21ClO4 m/z 383.00 (M+Na)+.
Reaction SMILES: ClCC[CH2:4][OH:5].NCCNC(NC1C=CC=CC=1)=O.[OH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(=O)(OCC)OCC>>[O:5]=[C:4]1[N:23]([CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH2:22][CH2:21][CH2:20][O:19]1
Reactant: O=C(NCCNCCCO)Nc1ccccc1
Reactant: OCCCCl
Agent: NCCNC(=O)Nc1ccccc1
Solvent: CCOC(=O)OCC
Product: O=C(NCCN1CCCOC1=O)Nc1ccccc1

Procedure:
When 3-chloropropanol is reacted with 1-(2-aminoethyl)-3-phenylurea and the resulting 1-[2-(3-hydroxypropylamino)ethyl]-3-phenylurea is reacted with diethyl carbonate according to the general processes of steps 1 and 2 of Example 2, there is obtained 1-[2-(tetrahydro-2-oxo-1,3-oxazin-3-yl)-ethyl]-3-phenylurea.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=O)=[C:7]([C:11]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:25][NH2:26]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([NH:26][CH3:25])=[O:23])=[C:7]([C:11]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 43 from [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid (Example 31) and methylamine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]1[O:30][CH:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:30][CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: c1ccc(C2CO2)cc1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC(O)c2ccccc2)c1

Procedure:
Alkylation reaction of phenol 58 with styrene oxide gave 2-(3-(3-(2-hydroxy-2-phenylethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.78 g, 58%): 1H NMR (400 MHz, CDCl3) δ 7.50-7.54 (m, 2H), 7.42-7.47 (m, 2H), 7.31-7.41 (m, 5H), 7.16-7.20 (m, 1H), 6.80-6.84 (m, 2H), 6.71 (dd, J=8.4, 2.2 Hz, 1H), 5.10 (dd, J=8.4, 3.2 Hz, 1H), 4.08 (d, J=6.4 Hz, 2H), 3.44-3.49 (m, 2H), 2.68 (t, J=7.4 Hz, 2H), 1.90-1.98 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][NH:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[I:30][C:31]1[CH:32]=[C:33]([S:42](Cl)(=[O:44])=[O:43])[CH:34]=[CH:35][C:36]=1[O:37][C:38]([F:41])([F:40])[F:39]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][N:13]2[S:42]([C:33]2[CH:34]=[CH:35][C:36]([O:37][C:38]([F:39])([F:40])[F:41])=[C:31]([I:30])[CH:32]=2)(=[O:44])=[O:43])=[O:11])=[CH:21][CH:22]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCN[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)c(I)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)c(I)c2)[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of the compound (40 mg) obtained in Step 3 and triethylamine (66 μl) in chloroform (0.4 ml) was added, with stirring at room temperature, 3-iodo-4-trifluoromethoxybenzenesulfonyl chloride (68 mg). After stirring at room temperature for 1 hr, the reaction mixture was directly purified by thin layer chromatography (methanol:chloroform=1:15) and recrystallized from water-containing methanol to give the title compound (53 mg).