Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)OCCN)(C)(C)C.N1C=CC=CC=1.[N+](C1C=C(CS(Cl)(=O)=O)C=CC=1)([O-])=O.[C:42]([Si:46]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[O:47][CH2:48][CH2:49][NH:50][S:51]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([N+:61]([O-])=O)[CH:56]=1)(=[O:53])=[O:52])([CH3:45])([CH3:44])[CH3:43]>ClCCl.CO.[Pd]>[NH2:61][C:57]1[CH:56]=[C:55]([CH2:54][S:51]([NH:50][CH2:49][CH2:48][O:47][Si:46]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)(=[O:52])=[O:53])[CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)[Si](OCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[Si](OCCN)(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)[Si](OCCNS(=O)(=O)Cc1cccc(N)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(tert-butyldiphenyl-silanyloxy)-ethylamine (0.76 g, 2.54 mmol) in dichloromethane (15 ml) and pyridine (0.21 ml, 2.54 mmol) at room temperature was added 3-nitro-alpha-toluenesulfonyl chloride (0.50 g, 2.12 mmol) in one portion and the reaction stirred overnight. The reaction was diluted with dichloromethane (35 ml), washed with aqueous copper sulfate and brine, dried over sodium sulfate and concentrated to give a crude product. The crude N-[2-(tert-butyldiphenyl-silanyloxy)-ethyl]-C-(3-nitrophenyl)-methanesulfonamide (theoretical 1.06 g, 2.13 mmol) was dissolved in methanol (30 ml) and placed under an atmosphere of nitrogen prior to the addition of 10% Pd/C (10 Wt %, 100 mg) in one portion. The reaction mixture was evacuated, placed under an atmosphere of hydrogen (1 bar) and stirred vigorously overnight. The reaction was filtered through celite and the filtrate was concentrated in vacuo to afford the crude reduced product. The crude C-(3-aminophenyl)-N-[2-(tert-butyldiphenylsilanyloxy)-ethyl]methanesulfonamide obtained above (theoretical 0.996 g) was dissolved in tetrahydrofuran (20 ml) and a 1M solution of tetrabutlyammonium fluoride in tetrahydrofuran (2.34 ml, 2.34 mmol) was added in one portion. The reaction was stirred at room temperature for 2 h then diluted with ethyl acetate (30 ml) and brine (30 ml), the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography using dichloromethane:methanol as eluent to give the named product (0.411 g, 84% over 3 steps); Rf (DCM:MeOH 95:5) 0.06; LCMS Rt=0.83 min, m/z (ES−) 229 (M−H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21]>C(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 112.3 %

Procedure:
A solution of amorphous ibandronic acid (5 g) in aqueous ethanol 96% (70 ml) was stirred at reflux temperature. Solid sodium hydroxide (0.63 g) was added. The obtained precipitate was cooled to room temperature and stirred for an additional 20 hours. The precipitate was isolated by vacuum filtration, washed with aqueous ethanol 96% (2×10 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain 6.0 g of ibandronate sodium crystal form Q6. Form Q6 can exhibit a weight loss of about 9% to about 10% in TGA.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][CH2:31][C@@H:30]3CO)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:33][CH2:32][CH2:31][C@@H:30]3[O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OC[C@H]1CCCN1c1nnc2ccc(F)cn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@H]1CCCN1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (430 mg, 1.40 mmol) was added to a solution of Intermediate 27a (220 mg, 0.93 mmol) and Et3N (190 mg, 1.86 mmol) in a DMF (2 mL) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (170 mg, 47%). LCMS (Method 1): Rt 4.45, m/z 393 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C@@H:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][C@H:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)N[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (44 mg, yield 98%).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].[N:17]#[C:18]Br>O1CCCC1.O>[Br:7][C:8]1[N:9]([C:18]#[N:17])[C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14]
Reactant: N#CBr
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(Br)c(Br)n(C#N)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Potassium t-butoxide (614 mg, 5.74 mmol) is added in portions at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (1.50 g, 4.56 mmol) in anhydrous tetrahydrofuran (20 mL). After 15 minutes a solution of cyanogen bromide (177 mg, 5.74 mmol) in tetrahydrofuran (5 mL) is added dropwise. The reaction solution is stirred at room temperature overnight as it turns cloudy. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride and dried over (Na2SO4). Evaporation of the solvent and crystallization of the residue from ether gives a white solid (1.20 g); mp 195.0°-197.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:21](=[O:23])[CH3:22])[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([CH:21]([OH:23])[CH3:22])[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([CH:21]([NH2:30])[CH3:22])[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: CC(O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-ethanone (150 mg, 0.493 mmol) in MeOH (5 mL) was added ammonium acetate (76 mg, 0.987 mmol). The reaction was stirred for 2 hours at room temperature. Sodium cyano borohydride (62 mg, 0.987) was added and the reaction was heated to 70° C. for 16 hours. LC-MS showed ˜1:1 ratio of alcohol and amine. The reaction was concentrated and purified by a reverse-phase C-18 preparative HPLC eluting with ACN—H2O having 0.1% acetic acid to give 1-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-ethanol (70 mg) and 1-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-ethylamine (20 mg).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH:11]=1.P(Cl)(Cl)([Cl:26])=O>ClCCCl>[ClH:26].[CH3:8][O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:5]3[N:6]([C:5]4[CH2:4][CH2:3][CH:2]([CH3:1])[N:6]=4)[CH:2]([CH3:1])[CH2:3][CH:4]=3)[C:12]=2[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Reactant: CC1CCC(=O)N1
Solvent: ClCCCl
Product: COc1ccc2c(c1)N(C1=CCC(C)N1C1=NC(C)CC1)c1ccccc1S2
Product: Cl
Yield: 8.6 %

Procedure:
Reaction of 5-methyl-2-pyrrolidinone, 2-methoxyphenothiazine and phosphorus oxychloride in 1,2-dichloroethane according to the procedure of Example 4 affords 2-METHOXY-10-[5-METHYL-1-(5-METHYL-1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE HYDROCHLORIDE (8.6% yield), m.p. 236.5°-238.5° C. (corr.), from ethanol-ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=2)=[O:8])[CH:2]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccnc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2cccnc2)cc1
Yield: 4 %

Procedure:
In a manner similar to that described in Example 3, 3-pyridinecarbonyl chloride (0.066 g, 0.00039 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol) (Example 1, Step (c)), and the resulting intermediate was hydrolyzed to give 0.003 g of 4-[4-((pyridin-3-yl)-carbonylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+299.
Reaction SMILES: C([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Cl)=[N:9][CH:8]=1)(C)(C)C.[CH3:15][CH:16]([CH3:21])[CH2:17][CH2:18][Mg]Br.C(O)(=O)C1C=CC=NC=1>>[CH3:15][CH:16]([CH3:21])[CH2:17][CH2:18][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:5])=[O:14])=[CH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reactant: CC(C)CC[Mg]Br
Agent: O=C(O)c1cccnc1
Product: CC(C)CCc1ccc(C(=O)O)cn1

Procedure:
6-(3-Methyl-butyl)-nicotinic acid is prepared by reacting 6-chloro-nicotinic acid tert-butly ester with 3-methyl-butylmagnesium bromide under Fürstner conditions as described for Nicotinic acid 2; LC-MS: tR=0.58 min, [M+1]+=194.30.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([OH:27])[C:24]([CH3:26])=[CH2:25])[CH:9]=1)([CH3:4])[CH3:3].I[CH2:31]I.C([Zn]CC)C>C(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:28])([CH3:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([C:24]2([CH3:31])[CH2:26][CH2:25]2)[OH:27])[CH:9]=1)([CH3:1])[CH3:3]
Reactant: ICI
Reactant: C=C(C)C(O)c1cc(CO[Si](C)(C)C(C)(C)C)ccc1-c1cc(OC)ccc1F
Agent: CC[Zn]CC
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C2(C)CC2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.5 %

Procedure:
A 100 mL round bottom flask was charged with 83.18D (0.92 g, 2.2 mmol), DCM (22 mL), and diiodomethane (available from Aldrich) (0.27 mL, 3.3 mmol) and cooled to 0° C. under N2. To the cold solution was added diethylzinc (1.0 M in heptane) (available from Aldrich) (3.3 mL, 3.3 mmol) at a rapid drip. The colorless mixture was stirred for 5 minutes. The cooling bath was removed, and the mixture was stirred for 2 hours at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase was washed with 1 M Na2S2O3 and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-15% EtOAc/hexane) to afford 83.18E (0.81 g, 85%) as a colorless oil.
Reaction SMILES: C[S:2]([CH3:4])=O.[CH2:5]([SH:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>Cl.II>[CH2:5]([S:17][S:2][CH2:4][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CS(C)=O
Reactant: CCCCCCCCCCCCS
Agent: Cl
Agent: II
Product: CCCCCCCCCCCCSSCCCCCCCCCCCC
Temperature: 60 °C
Yield: 89.6 %

Procedure:
A mixture of 9 ml of DMSO (127 mmole), 12 ml of 1-dodecanethiol (50 mmole), 0.1 ml of 37 percent hydrochloric acid (1.2 mmole), and 10.8 mg of iodine (0.085 mmole as HI) was heated by a bath, while stirring magnetically, at about 60°C. After one and a fourth hours, the lower phase became amber colored. The mixture was cooled with stirring to produce fine crystals. These were filtered off and rinsed with DMSO. Recrystallization from acetone gave 9.02 g of didodecyl disulfide (90 percent of theory). Mp, 33°-5°C. (reported, 33°-4°C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38].[C:40]1(C)C=C[C:43]([S:46](O)(=O)=O)=[CH:42][CH:41]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][CH:10]([CH:26]([S:46][CH2:43][CH2:42][CH2:41][CH3:40])[S:39][CH2:35][CH2:36][CH2:37][CH3:38])[C:9]1=[O:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCS
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Product: CCCCSC(SCCCC)C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 144 h

Procedure:
0.5 g of 5-Biphenyl-4-ylmethyl-3-[1-dimethylamino-meth-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) are added to 5 ml of n-butane-1-thiol. After the addition of 0.2 g of p-toluenesulfonic acid the mixture is stirred for 6 days at 25° C., then heated to 60° C. for 16 hours. The mixture is then quenched by addition of 5 ml of an 8% aqueous bicarbonate solution and any remaining n-butane-1-thiol distilled off under reduced pressure at 40° C. The aqueous phase is extracted 3 times with 5 ml ethyl acetate each and the combined organic phase evaporated to dryness at 40° C. under reduced pressure. The residue is purified by column chromatography (heptane: ethyl acetate 75:25) to afford (3R/S,5S)-5-biphenyl-4-ylmethyl-3-(bis-butylsulfanyl-methyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (16-a, R1=Boc, R9=nBu, R9=nBu, Y=S). Ratio of C-3 diastereomers determined as 70:30 ((3S,5S):(3R,5S) diastereomers, respectively). 1H NMR (CDCl3): Data for mixture of diastereomers: 0.86-0.96 (6H), 1.32-1.47 (4H), 1.50-1.68 (4H), 1.62 (9H), 1.94-2.30 (2H), 2.48-2.74 (4H), 2.80-2.89 (2H), 3.10-3.16 (1H), 3.55-3.59 (1H, minor stereoisomer), 4.23-4.31 (1H, minor stereoisomer), 4.30 (1H), 4.38 (1H, minor stereoisomer), 4.43-4.47 (1H), 7.27-7.30 (2H), 7.32-7.40 (1H), 7.44-7.50 (2H), 7.56-7.65 (4H).
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[O:21][CH3:22].Cl.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1>>[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:26]2[CH2:27][CH2:28][CH2:29][C:24]2=[O:9])=[CH:15][C:14]=1[O:21][CH3:22]
Reactant: c1ccccc1
Reactant: COc1cc(C=O)ccc1O
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: COc1cc(C=C2CCCC2=O)ccc1O
Temperature: 30 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 4-hydroxy-3-methoxybenzaldehyde and 200 mL benzene were added to a round bottom flask and heated under refluxing for 20 h. The resulting solution was cooled to 30° C. and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexan/ethanol to yield a light yellow flaky crystal product with a yield of 92.6%
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1=[O:14])=[CH2:2].[C:15](#[N:18])[CH:16]=[CH2:17].C1(C=CC(O)=CC=1)O.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.CN(C)C=O>[C:15]([CH2:16][CH2:17][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][CH2:4][O:3][CH:1]=[CH2:2])[C:7]1=[O:14])#[N:18]
Reactant: C=CC#N
Reactant: C=COCCN1C(=O)NC(C)(C)C1=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)N(CCC#N)C(C)(C)C1=O

Procedure:
A mixture of 237.8 g (1.2 mols) of 3-(2-vinyloxyethyl)-5,5-dimethylhydantoin, prepared as described in Example 1, 79.6 g (1.2 mols+20% excess) of acrylonitrile, 0.5 g of hydroquinone, 2.4 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol and 360 ml of dimethylformamide is allowed to react for 27 hours at 81°-85° C. The solution is then concentrated on a rotary evaporator at 90° C. under vacuum from a waterpump and the residue is dried to constant weight at 90° C. and 13.3 Pa. 300.4 g (99.6% of theory) of a dark brown, crystalline crude product are obtained and are purified by distillation. 260.8 g (86.5% of theory) of a crystalline distillate boiling at 147°-150° C. are obtained. After recrystallisation from ether, the product melts at 54.8°-55.5° C.
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([CH2:35][NH:36]C(=O)C)[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:17]([NH:28][CH2:29][CH3:30])=[N:18][C:19]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)(=O)C.CC(N(C(C)C)CC1C=CC=CC=1)C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH3:72][S:73](Cl)(=[O:75])=[O:74]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:72][S:73]([O:4][C:5]1[N:6]=[C:7]([CH2:35][NH:36][S:73]([CH3:72])(=[O:75])=[O:74])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:17]([NH:28][CH2:29][CH3:30])=[N:18][C:19]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)(=[O:75])=[O:74]
Reactant: CS(=O)(=O)Cl
Reactant: CCNc1nc2ccc(OC)cc2cc1Cc1c(OC(C)=O)nc(CNC(C)=O)c2cc(OC)c(OC)cc12
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)N(Cc1ccccc1)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(OS(C)(=O)=O)nc(CNS(C)(=O)=O)c2cc(OC)c(OC)cc12
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
The other portion of the residue CCH 42006-2 (see preparation of compound 56) was transferred in a 5 mL microwave vial equipped with a magnetic stirrer before addition of diisopropylaminomethyl-polystyrene resin (3 mmol/g, 86 mg, 258 μmol), DMAP (2 mg, 16 μmol) and methanesulfonyl chloride (25 μL, 323 μmol) and the reaction mixture was stirred for 20 min at 100° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (30 mL), filtered through cotton wool, then washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methylsulfonamidomethyl)isoquinolin-3-yl methanesulfonate as a pale yellow solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)CCl.O>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([C:22](=[O:23])[C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=3)=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[O:9]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of methyl 3,4-methylenedioxyphenylacetate (5.4 g, 28 mmol) in ClCH2CH2Cl (100 mL) was added 4-nitrobenzoic acid (7.2 g, 43 mmol) and P2O5 (18 g) at room temperature under argon. The mixture was refluxed for 28 h, cooled to room temperature, then cold water was added slowly. The resulting mixture was carefully neutralized with solid K2CO3, and extracted with 1:1 hexane/EtOAc (2×300 mL). The combined extracts were washed with water and brine, and dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was separated by chromatography (3:1 hexane/EtOAc) to afford the title compound as a yellow solid (4.7 g, 14 mmol, 50%). 1H NMR (CDCl3) 8.32 (d, 2H, J=8.5), 7.92 (d, 2H, J=8.5), 6.85 (s, 1H), 6.81 (s, 1H), 6.07 (s, 2H), 3.88 (s, 2H), 3.63 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17]OC(=O)C(C)(C)C)[S:15][CH:16]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.Cl.C(N1CCNCC1)(C)C.O[N:37]1[C:41]2C=[CH:43][CH:44]=[CH:45][C:40]=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[N:13]=[C:14]([CH2:17][N:37]3[CH2:43][CH2:44][CH2:45][CH2:40][CH2:41]3)[S:15][CH:16]=2)=[O:11])[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCN(C(=O)c2csc(COC(=O)C(C)(C)C)n2)CC1
Reactant: On1nnc2ccccc21
Agent: CC(C)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)N1CCN(C(=O)c2csc(CN3CCCCC3)n2)CC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
2,2-Dimethyl-Propionic acid 4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester. The crude product from Step A (6.42 g, 24.2 mmol), 1-isopropyl-piperazine dihydrochloride (5.36 g., 26.68 mmol) and 1-hydroxybenzotriazole (4.915 g., 36.38 mmol) were dissolved into a mixture of N-methylmorpholine (14.72 g., 101.20 mmol) and DCM (120 mL). The mixture was stirred for 30 min under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.97 g, 36.4 mmol) was added, and the reaction mixture was stirred for 18 h at rt. The reaction was quenched by the addition of 1 M NaOH (25 mL), and was stirred for 1 h. The mixture was diluted with water and extracted with DCM (3×60 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to yield dark brown crude oil (6.2 g). The crude product was purified on silica gel column using 30-50% acetone-DCM to give the title compound as a brown oil (3.9 g, 46%). 1H NMR (500 MHz, CDCl3): 7.89 (s, 1H), 5.38 (s, 2H), 3.90-3.84 (m, 2H), 3.81-3.75 (m, 2H), 2.75-2.69 (m, 1H), 2.62-2.50 (m, 4H), 1.27-1.23 (s, 9H), 1.05 (d, J=6.3, 6H).