Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1.[Cl-].[Na+]>C1COCC1>[Cl:18][C:19]1[N:20]=[N:21][C:22]([O:16][CH2:15][C:14]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[N:11][O:12][C:13]=2[CH3:17])=[CH:23][CH:24]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 632 mg, 14 mmol) in THF (21 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.0 g, 14 mmol) in THF (42 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of 3,6-dichloropyridazine (2.2 g, 14 mmol) in THF (42 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (4.3 g, 92%) which was obtained as an off white solid. MS: m/e=320.0 [M+H]+.
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][N:16](C([O:21][CH2:22][C:23]3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.O.C([OH:32])C>C(O)(=O)C.[C].[Pd]>[C:22]([OH:32])(=[O:21])[CH3:23].[NH:16]1[CH2:15][CH2:14][CH:13]([C:1]2[N:2]=[N:3][N:4]3[C:9]=2[C:8]2[CH:10]=[CH:11][NH:12][C:7]=2[N:6]=[CH:5]3)[CH2:18][CH2:17]1
Reactant: CCO
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: c1cc2c(ncn3nnc(C4CCNCC4)c23)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
5% Palladium-carbon (0.87 g) was added to benzyl 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (4.88 g, 13.0 mmol) obtained in Synthetic Examplea 26 in a mixture of acetic acid (60 mL), water (6 mL) and ethanol (10 mL), and after then the reaction system was flushed with hydrogen, the reaction mixture was stirred at room temperature for one day and then filtered. The filtrate was concentrated, and the resulting yellow solid was washed with ethanol to give the title compound as a colorless solid (3.30 g, yield 84%).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH:14]2[CH:10]([C:11]([CH3:26])([CH3:25])[NH:12][CH:13]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](O)=O.C=O>[OH-].[Na+]>[CH2:1]([N:8]1[C:15](=[O:16])[CH:14]2[CH:10]([C:11]([CH3:25])([CH3:26])[N:12]([CH3:28])[CH:13]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)NC(Cc2ccc(Br)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C21
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(Cc2ccc(Br)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Temperature: 100 °C
Yield: 85.9 %

Procedure:
A mixture of 3.88 g (9.1 mmol) of (3aRS,4RS,6aSR)-2-benzyl-4-(4-bromo-benzyl)-6,6-dimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione, 85% formic acid (4.9 g, 90 mmol) and 35% formalin solution (2.6 g, 30 mmol) were heated to 100° C. for 5.5 hours. After cooling 1N NaOH (50 ml) was added and the mixture was extracted four times with dichloromethane. The organic phase was concentrated and the residue was separated chromatographically (hexane/ethyl acetate 3:1+1% triethylamine). 3.45 g of (3aRS, 4RS,6aSR)-2-benzyl-4-(4-bromobenzyl)-5,6,6-trimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione were isolated as a yellowish oil. FAB-MS: 441 ([M+H]+, 40); 271 (100); 212 (5); 169 (11); 136 (14); 110 (26); 91 (42).
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][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1)([CH3:26])[CH3:25].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[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][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([C:24]([F:23])([CH3:25])[CH3:26])[CH:31]=2)=[O:34])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC
Yield: 44.9 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (95 mg, 0.36 mmol) were reacted according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea as a colorless solid (63 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 10.50 (brs, 1H), 9.15 (s, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.40-7.45 (m, 2H), 7.32 (m, 1H), 7.00 (m, 1H), 6.14 (s, 1H), 3.99-4.00 (2×s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 468 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])#[N:2].Cl.C(O)(=[O:21])C>>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])(=[O:21])[NH2:2]
Reactant: N#Cc1cc2c(=O)c3ccccc3ccn2c1
Reactant: CC(=O)O
Agent: Cl
Product: NC(=O)c1cc2c(=O)c3ccccc3ccn2c1
Temperature: 25 °C

Procedure:
2-Cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid is refluxed for 2 hours. It is then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution is left to cool to room temperature and filtered to afford 2-carbamoyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])C)C.ON1C2C=CC=CC=2N=N1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][CH3:46])[N:39]=2)=[CH:34]\[C:35](O)=[O:36])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].N1CCCCC1>CN(C)C=O.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30](/[C:33](/[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][CH3:46])[N:39]=2)=[CH:34]\[C:35]([N:10]2[CH2:9][CH2:8][CH2:7][CH2:12]2)=[O:36])=[CH:31][CH:32]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: COc1nc(/C(=C/C(=O)O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(/C(=C/C(=O)N2CCCC2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reaction time: 0.25 h
Yield: 40 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg) and 1-hydroxybenzotriazole (61 mg) were added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-enoic acid obtained in Reference Example 4-6 (137 mg) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 15 minutes. Thereafter, piperidine (50 mg) was added and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate. This was sequentially washed with saturated aqueous sodium bicarbonate, water and brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)-1-(pyrrolidin-1-yl)prop-2-en-1-one as a colorless oil (63 mg, 40%).
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=[O:34])=[CH:25][CH:24]=1.O>O1CCCC1.C(O)(=O)C>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:23]=[CH:24][CH:25]=2)[OH:34])=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(Br)ccc1OCc1ccccc1
Reactant: O=Cc1ccnc2ccccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(O)c2ccnc3ccccc23)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
25 ml of tert.-butyllithium solution (1.4M in hexane) are added dropwise at -70° within 10 minutes to 10 g of 4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 100 ml of tetrahydrofuran. After stirring at -70° for 1 hour, 5 g of quinoline-4-carbaldehyde dissolved in 50 ml of tetrahydrofuran are added dropwise within 30 minutes. The reaction mixture is stirred at -40° for 1 hour and at -5° for 1 hour, poured into 200 ml of water and adjusted to pH 4 with glacial acetic acid. The mixture is extracted three times with 50 ml of ether each time. The combined ether phases are washed with water, dried over sodium sulfate and evaporated. There is obtained α-[4-(benzyloxy)-3-methoxyphenyl]-4-quinolinemethanol as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[C:26]([O:30][C:31]([N:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[C:26]([O:30][C:31]([N:33]1[CH2:36][CH:35]([C:37]([CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)C2C(=O)OC(C)(C)OC2=O)C1
Reaction time: 8 h

Procedure:
Meldrum's acid (0.85 g, 5.97 mmol), DCC (1.22 g, 5.97 mmol), and DMAP (1.45 g, 11.94 mmol) were successively added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.2 g, 5.97 mmol) in dichloromethane (25 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of cyclohexane (25 mL). The precipitate of dicyclohexyl urea was then filtered and rinsed with diethyl ether (100 mL). The mother liquors were diluted with DCM (100 mL) and washed with a 1M solution of aqueous HCl (2×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. After trituration in diethyl ether the title compound was obtained as a white solid (1.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13](S(C)(=O)=O)[N:14]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=2)[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Reactant: N#Cc1ccc(NCCN)nc1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)c2C1

Procedure:
Reaction of tert-butyl 4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate and 2-(2-aminoethylamino)-5-cyanopyridine gave tert-butyl 4-(2,4-dichlorophenyl)-2-({2-[(5-cyano(2-pyridyl))-amino]ethyl}amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([N+:33]([O-])=O)[CH:27]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].[CH:37](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[NH:32][CH:37]=[N:33][C:28]=3[CH:27]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36]
Reactant: CCCC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reactant: O=CO
Agent: [Pd]
Product: CCCC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1

Procedure:
Prepared from 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(4-propyl-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[NH:4][C@H:5]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[C:18]3[C:23]([CH:24]=[CH:25][C:15]=2[N:14]=1)=[CH:22][C:21]1[C:26]2[C:31]([CH2:32][O:33][C:20]=1[CH:19]=3)=[CH:30][C:29]([C:34]1[NH:38][C:37]([C@@H:39]3[CH2:43][C@H:42]([CH2:44][O:45][CH3:46])[CH2:41][NH:40]3)=[N:36][CH:35]=1)=[CH:28][CH:27]=2)=[O:7].[CH3:54][O:55][C:56]([NH:58][C@@H:59]([CH:63]([CH3:65])[CH3:64])[C:60](O)=[O:61])=[O:57].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:54][O:55][C:56](=[O:57])[NH:58][C@@H:59]([CH:63]([CH3:64])[CH3:65])[C:60]([N:40]1[CH2:41][C@@H:42]([CH2:44][O:45][CH3:46])[CH2:43][C@H:39]1[C:37]1[NH:38][C:34]([C:29]2[CH:30]=[C:31]3[CH2:32][O:33][C:20]4[CH:19]=[C:18]5[C:23]([CH:24]=[CH:25][C:15]6[N:14]=[C:13]([C@@H:9]7[CH2:10][CH2:11][CH2:12][N:8]7[C:6](=[O:7])[C@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:53])[C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)[NH:17][C:16]=65)=[CH:22][C:21]=4[C:26]3=[CH:27][CH:28]=2)=[CH:35][N:36]=1)=[O:61]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl{(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (55 mg, 0.077 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14 mg, 0.077 mmol), HATU (32 mg, 0.085 mmol) and 0.4 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. The product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate. The eluent was concentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (30.7 mg)
Reaction SMILES: [I-].[CH:2]1([N+:12]2([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH2:18]>>[OH-:18].[CH:2]1([N+:12]2([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O
Agent: C[N+]1(C2CCCCCCCCC2)CCCC1
Agent: [I-]
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-cyclodecyl-N-methyl-pyrrolidinium iodide (45 gm; 0.128 mol) was dissolved in 150 ml water in a 500 ml plastic bottle. To the solution, 160 gm of Ion-Exchange Resin-OH (BIO RAD® AH1-X8) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solids were rinsed with an additional 85 ml of water. The reaction afforded 0.12 mole of the SDA (N-cyclodecyl-N-methyl-pyrrolidinium hydroxide) as indicated by titration analysis with 0.1N HCl.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([OH:9])[CH2:4]1.[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C)C=O>[Si:10]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([OH:9])[CH2:4]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1CCC[C@@H](O)C1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1CCC[C@@H](O)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10.5 g of (1S,3R)/(1R,3S)-3-hydroxymethylcyclohexanol are dissolved in 300 ml of dimethylformamide, and 23 ml of tert-butyldiphenylsilanyl chloride, 8.0 g of imidazole and 200 mg of dimethylaminopyridine are added. The mixture is stirred at room temperature for 12 hours. The dimethylformamide is removed under reduced pressure and the residue is dissolved in 300 ml of ethyl acetate and washed five times with in each case 100 ml of water. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 27.0 g of (1S,3R)/(1R,3S)-3-(tert-butyldiphenylsilanyloxymethyl)cyclohexanol as an oil. C23H32O2Si (368.6), Rf(n-heptane:ethyl acetate=1:1)=0.42.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[NH:29][C:28](=[O:30])[O:27][N:26]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(O)C.C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[NH:29][C:28](=[O:30])[O:27][N:26]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3noc(=O)[nH]3)ccc2c1=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3noc(=O)[nH]3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Tert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.18 g, 0.37 mmol) was dissolved in ethanol (4 ml) and a solution (4 ml) of 4N hydrogen chloride in ethyl acetate was added. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether (2 ml) and recrystallized from ethyl acetate-ethanol (20:1) to give 3-(aminomethyl)-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1(2H)-isoquinolinone hydrochloride (0.12 g, 80%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]#[N:26].O>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]#[N:26])[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)c(Oc2cc(Cl)nc(-c3ccccc3)n2)c1
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To 4,6-dichloro-2-phenylpyrimidine (1.5 g, 6.7 mmol) in acetonitrile (20 mL) was added Cs2CO3 (2.4 g, 7.4 mmol) and 3-hydroxy-4-(benzyloxy)benzonitrile (1.5 g, 6.5 mmol). After stirring for 24 hours, water was added to the reaction mixture and the resulting solid was collected by suction filtration to give 2.6 g of 3-[(6-chloro-2-phenylpyrimidin-4-yl)oxy]-4-(benzyloxy)benzonitrile.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 64.8 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 23.3 g of triethylamine in 50 ml of toluene was dropped into the above solution at 0° C. to -5° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of triethylamine hydrochloride was recovered by filtration and the filtrate was distilled to recover toluene, whereby 16.0 g of γ-triethoxysilylpropyl isocyanate was obtained at a fraction having a boiling point of 88° C. to 91° C. under 4.5 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH2:9].[CH3:10][C:11](=O)[C:12](=O)[C:13](=[O:15])[CH3:14].C(#[N:20])C>>[CH3:10][C:11]1[NH:20][C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])=[N:9][C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: CC#N
Reactant: CC(=O)C(=O)C(C)=O
Reactant: Cc1cnccc1CN
Product: CC(=O)c1nc(-c2ccncc2C)[nH]c1C
Temperature: -10 °C

Procedure:
A mixture of 7.1 g of 3-methyl-4-pyridylmethylamine, 6.25 g of 2,3,4-pentanetrione, 3-oxime and 125 ml of acetonitrile was stirred at reflux temperature for 5 hours, then cooled at -10° C. The resulting precipitate was collected, washed with cold acetonitrile, dried and then recrystallized from a mixture of chloroform and hexane, giving 4.5 g of the desired compound, mp 185°-187° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:60][CH:61]=[CH:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 3 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (52 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compound (17 mg).