Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=O>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[N+:14]([O-:16])=[O:15])[CH2:3][N:2]([CH3:1])[CH2:11][CH2:10]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])C(=O)N(C)CC2
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C)CC2
Temperature: 80 °C
Yield: 67.5 %

Procedure:
To a solution of 2-methyl-6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-isoquinolinone (4.7 g, 20 mmol) in THF (500 mL) was added 2.0 M BH3 in THF (49.8 mL, 100 mmol). The resulting solution was heated at reflux for 20 h. The mixture was quenched via careful addition of MeOH (50 mL), the resulting solution was concentrated under reduced pressure and the residue was heated at 80° C. with 2N HCl for 3 h. The reation was cooled, adjusted to basic pH via cautious addition of aqueous NH4OH, and extracted with dichloromethane. The combined organic layers were dried and concentrated under reduced pressure to give 6-methoxy-2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (3 g crude, 67%).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(-c2ccccc2)cc1
Product: O=C(O)c1ccncc1NCc1ccc(-c2ccccc2)cc1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 4-phenylbenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.55 (br s, 1H), 8.17 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.71 (m, 4H), 7.58 (d, 1H, J=5.0 Hz), 7.32-7.48 (m, 5H), 4.62 (s, 2H). [M+H] calc'd for C19H16N2O2, 305. Found 305.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ClCCl.[C:60]([O:64][C:65]([N:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][CH2:75][NH2:76])[CH2:69][CH2:68]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]>C(N(CC)CC)C>[C:60]([O:64][C:65]([N:67]1[CH2:68][CH2:69][N:70]([CH2:73][CH2:74][CH2:75][NH:76][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:71][CH2:72]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NCCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
To a mixture of 0.105 g (0.23 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0988 g (0.26 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 1 mL of dichloromethane, 0.2 mL of triethylamine was added followed by 0.0199 g (0.13 mmole) of 4-(3-amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester. After stirring 1.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-water (gradient, 5:95-0:100) to give 0.0609 g of 4-{3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (I-94).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:15])=[CH:4][CH:3]=1
Reactant: Oc1nccc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 7-bromoisoquinolin-1-ol (1.0 g, 4.46 mmol, 1.00 equiv) in POCl3 (5 mL). The reaction mixture was stirred for 60 min at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 20 mL of DCM, washed with 3×10 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The title compound was obtained as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]CC=C)=[O:22])[CH:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([SiH3])C=CC=CC=1.O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:29]=1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[C:21]([OH:23])=[O:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)c1cccc(OC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cccc(OC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)c1
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
Pd(PPh3)4 (23.1 mg, 0.02 mmol) and 3-((allyloxy)carbonyl)phenyl 3,4,5-tris(benzyloxy)benzoate (600 mg, 1 mmol) were dissolved in CH2Cl2 (3 mL) and cooled in an ice bath. To the resulting solution was added phenylsilane (216 mg, 2 mmol). After stirring for 15 min, H2O (5 mL) was added dropwise, resulting in a precipitate. The solid was washed successively with ethyl acetate, dichloromethane, and water. The combined organic layers were concentrated in vacuo to half-volume and extracted with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (378 mg, 68%).
Reaction SMILES: N1C=CC=CC=1C.Cl[S:9]([OH:12])(=[O:11])=[O:10].[C:13]1([C:19]2[N:20]=[CH:21][C:22]([N:31]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]([NH2:43])=[O:42])[CH:32]([CH3:34])[CH3:33])=[N:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.ClCCl>[C:13]1([C:19]2[N:20]=[CH:21][C:22]([N:31]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]([NH:43][S:9](=[O:11])(=[O:10])[OH:12])=[O:42])[CH:32]([CH3:34])[CH3:33])=[N:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)N(CCCCOCC(N)=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: O=S(=O)(O)Cl
Solvent: Cc1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)N(CCCCOCC(=O)NS(=O)(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, a solution of 1.443 g of 2-picoline in 1.7 ml of 1,2-dichloroethane was cooled to −10° C. A solution of chlorosulfonic acid in 3.5 ml of 1,2-dichloroethane was added dropwise at 0° C. or lower and, after stirring for 15 minutes, 712 mg of 2-[4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy]acetamide was added. The reaction solution was heated to 75° C. and air-cooled to room temperature after stirring for 2 hours. The reaction solution was diluted with dichloromethane and then washed in turn with an aqueous 0.6M sodium hydrogen sulfate and water. The reaction solution was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 798 mg of N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic acid.
Reaction SMILES: FC1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[N:12]1C=CC=C(C(O)=O)N=1.FC1N=C(C(O)=O)C=CC=1>>[N:12]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[N:7]=1
Reactant: O=C(O)c1cccnn1
Reactant: NNC(=O)c1cccc(F)n1
Agent: O=C(O)c1cccc(F)n1
Product: NNC(=O)c1cccnn1

Procedure:
3-Pyridazinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 3-pyridazine carboxylic acid (CAS [2164-61-6], commercially available e.g. from Apollo Scientific, Shanghai AOKChem or Manchester Organics) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][CH:10]=1)=[O:8].I[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]([CH2:32][CH3:33])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][CH:10]=1)=[O:8]
Reactant: CCI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(Cl)c4)cc3)c2)o1
Product: CCN(Cc1cccc(Cl)c1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-(3-Chlorobenzyl)-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(3-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, b), 7.58-7.34,(8H, m), 7.24,(1H, b), 4.71-4.55,(2H, m), 3.25,(2H, b), 2.56,(3H, s), 2.32,(3H, s), 1.09,(3H, b). LCMS; retention time 3.67 min, MH+ 446/448.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][CH2:27]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][CH2:27]3)=[CH:5][CH:4]=1
Reactant: Brc1cccc2c1C=CC2
Reactant: C[Si](C)(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[Si](C)(C)c1ccc(-c2cccc3c2C=CC3)cc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
In a 500-ml flask, 10.0 g (51.5 mmol) of 4-trimethylsilylphenylboronic acid and 200 ml of dimethoethane were added to make a solution and thereafter, 27.3 g (128 mmol) of potassium phosphate, 100 ml of water, 8.37 g (43.0 mmol) of 4-bromoindene, 0.22 g (0.86 mmol) of triphenylphosphine, and 0.300 g (0.430 mmol) of PdCl2(PPh3)2 were added in sequence and stirred under reflux for 12 hours. After cooling to room temperature, 100 ml of water was added. The organic phase was separated and then, the aqueous phase was extracted twice with 100 ml of ethyl acetate. The obtained organic phases were mixed and washed with a saline solution, and the resulting organic phase was dried by adding sodium sulfate. Sodium sulfate was filtered, and the solvent was removed by distillation under reduced pressure. The residue was purified on a silica gel column to obtain 9.0 g (yield: 79%) of 4-(4-trimethylsilyl-phenyl)-indene as a yellow liquid.
Reaction SMILES: Cl.[NH:2]([C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.CC(C)=O>S1(CCCC1)(=O)=O>[NH:2]([C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1ccc(Nc2ncc(Cl)c(Nc3ccccc3)n2)cc1
Temperature: 140 °C
Yield: 96.5 %

Procedure:
Ethereal hydrogen chloride (1.0M; 10 ml, 10.0 mmol) was added to a solution of 4-anilino-2,5-dichloropyrimidine (Method 2; 2.41 g, 10.0 mmol) and 4-aminobenzoic acid (1.10 g, 8.0 mmol) in sulpholane (10 ml) and the mixture was heated at 140° C. for 3 hours. The mixture was left to cool and acetone (75 ml) was added. The insoluble solid was collected by filtration and washed with acetone (50 ml) to give the product (2.63 g, 97%). NMR: 7.25 (t, 1H), 7.4 (t, 2H), 7.55-7.65 (m, 4H), 7.7 (d, 2H), 8.35 (s, 1H), 9.6 (br s, 1H), 10.4 (br s, 1H); MS (MH+): 341, 343.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C:6]([CH3:12])=[C:7]([CH3:11])[C:8]=1[C:9]#[N:10])[CH3:2].[C:13]([N:21]=[C:22]=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:9]([C:8]1[C:7]([CH3:11])=[C:6]([CH3:12])[S:5][C:4]=1[N:3]([CH2:1][CH3:2])[C:22]([NH:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23])#[N:10]
Reactant: CCNc1sc(C)c(C)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Product: CCN(C(=O)NC(=O)c1ccccc1)c1sc(C)c(C)c1C#N

Procedure:
Prepared in a similar manner to Example 1a from 2-(ethylamino)-4,5-dimethylthiophene-3-carbonitrile (Example 21b) and benzoyl isocyanate. MS 328 (MH+).
Reaction SMILES: [C:1]1([Si](OC)(OC)[O:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.CO[Si](CCC[CH:48]1[CH2:53][C:52](=[O:54])[O:51][C:49]1=[O:50])(OC)OC.SCCC[Si](OCC)(OCC)OCC.Cl.C(OCC(O)C)C.[OH-].[C:78]1([S+:84]([C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)[C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>O.C(O)C.CC(C)=O>[C:52]([O-:51])(=[O:54])[CH2:53][CH2:48][C:49]([O-:50])=[O:8].[C:91]1([S+:84]([C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)[C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=1.[C:1]1([S+:84]([C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO[Si](CCCC1CC(=O)OC1=O)(OC)OC
Reactant: CO[Si](OC)(OC)c1ccccc1
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](CCCS)(OCC)OCC
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.80 g of phenyltrimethoxysilane, 70.71 g of tetraethoxysilane, 17.20 g of methyltriethoxysilane, 0.14 g of trimethoxysilylpropyl succinic anhydride, 5.78 g of mercaptopropyltriethoxysilane, and 150 g of acetone were charged into a 500 ml flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 32.31 g of a 0.01 M hydrochloric acid aqueous solution was added to the mixed solution. The reaction was carried out for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol, water and hydrochloric acid being reaction by-products were distilled off under reduced pressure to obtain a hydrolysis-condensation product. To the hydrolysis-condensation product, 1.36 g of a 10% by weight triphenylsulfonium hydroxide aqueous solution was added to obtain a triphenylsulfonium succinic acid salt-containing Si polymer. The obtained polymer corresponded to a polymer having five types of unit structures of Formula (3-31). The molecular weight Mw of the obtained polymer measured by GPC was found to be 1,500 in terms of polystyrene.
Reaction SMILES: Br[C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([OH:53])(=[O:52])[CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[CH:51]>CN(C=O)C.[Cu]I>[C:11]([C:8]1[C:7](=[O:13])[NH:6][C:5]2[S:14][C:2]([C:51]#[C:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([OH:53])=[O:52])=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[C:9]=1[OH:10])#[N:12]
Reactant: C#CCCCCC(=O)O
Reactant: N#Cc1c(O)c2c(-c3ccccc3)c(Br)sc2[nH]c1=O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1c(O)c2c(-c3ccccc3)c(C#CCCCCC(=O)O)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-Bromo-4-hydroxy-6-oxo-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (150 mg, 0.45 mmol) in 4.5 mL DMF was added diethylamine (0.48 mL, 4.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (10 mg, 0.015 mmol), and triphenylphosphine (36 mg, 0.12 mmol). The resulting mixture was stirred at rt for 5 min, after which hept-6-ynoic acid (0.19 mL, 1.5 mmol) was added. The reaction was then heated to 120° C. using microwave for 25 min, filtered, concentrated and purified by reverse phase HPLC. MS (ESI) m/e 393 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 1.28–1.56 (m, 4H), 2.12–2.30 (m, 4H), 7.20–7.35 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([CH:26]([CH2:29][CH3:30])[CH2:27][NH2:28])[CH3:25]>>[CH2:24]([CH:26]([CH2:29][CH3:30])[CH2:27][NH:28][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:25]
Reactant: CCC(CC)CN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: CCC(CC)CNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 95 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2-ethylbutylamine instead of methylamine, to the title compound (121 mg, 95%) which was obtained as an off white solid. MS: m/e=394.4 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29].[Cl-].[NH4+]>C1COCC1>[Br:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCCCBr
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.82 mL) in THF (30 mL) was added n-butyllithium (2.5M in hexanes, 16.4 mL) at 0° C. and the mixture was stirred for 30 min at this temperature before being cooled to −78° C. Ethyl isobutyrate (5 mL) was added dropwise and the resultant mixture was stirred at −78° C. for 1 h before addition of 1,7-dibromoheptane (6.4 mL). The reaction mixture was stirred at −78° C. for 1 h then at RT for 2 h before being poured into saturated ammonium chloride solution. The solution was extracted with ethyl acetate (×2) then the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% ethyl acetate in cyclohexane to give the subtitled compound as a colourless liquid. Yield 1.27 g.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[NH2:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>C(O)(=O)C>[OH:19][C:15]1[CH:14]=[C:13]([N:12]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)c1
Temperature: 0 °C

Procedure:
A mixture of 25.0 g of 3,4,5,6-tetrahydrophthalic anhydride (THPA), 17.9 g of 3-aminophenol and 350 mL of glacial acetic acid was refluxed for 1 hour, then cooled and poured slowly into 1400 mL of ice-water. The resulting mixture was filtered, The collected solids were washed with cold water and dried (oven, reduced pressure) to give N-(3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (1A), as yellow crystals, mp.: 196°-197.5° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH:46]([CH2:50][NH2:51])[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].CS(C)=O>C(#N)C.ClCCl>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:51][CH2:50][CH:46]4[CH2:47][CH2:48][CH2:49][N:44]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:45]4)=[O:4])=[CH:6][CH2:7][C:8]3=[CH:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Solvent: CC#N
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccccc1-c1ccc(C(=O)N2C=C3CC=C(C(=O)NCC4CCCN(C(=O)OC(C)(C)C)C4)N3Cc3ccccc32)cc1C
Temperature: 80 °C
Yield: 128 %

Procedure:
To a suspension of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 9 (0.54 g, 1.0 mmol) and 3-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.43 g, 2.0 mmol) in dry acetonitrile (5 mL) was added dimethylsulfoxide (0.35 mL, 4.9 mmol) and the reaction mixture heated to 80° C. under nitrogen for 3 days. The cooled reaction mixture was diluted with dichloromethane (25 mL), washed with water (2×25 mL) and brine (25 mL), dried over anhydrous potassium carbonate, filtered and concentrated in vacuo to afford a brown oil (0.81 g). Purification by flash chromatography using a solvent gradient of 3 to 20% ethyl acetate in dichloromethane gave the title compound (0.45 g) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH:12]([OH:15])[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[C:12](=[O:15])[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A solution of 5-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-2-ol (455 mg, 1.88 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with pyridine (0.38 mL, 4.6 mmol), followed by Dess-Martin periodinane (1.95 g, 4.6 mmol) and warmed to ambient temperature. After 2 h, 3 drops of H2O were added. After 0.5 h, the reaction was quenched with saturated NaHCO3, saturated Na2SO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried and concentrated in vacuo. Purification by silica gel chromatography gave the target compound (200 mg, 44%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.50 (m, 1 H) 1.51-1.58 (m, 1 H) 2.11 (dd, 1 H) 2.21-2.37 (m, 3 H) 2.37-2.45 (m, 1 H) 7.04 (dd, 1H) 7.32 (d, 1 H) 7.37 (d, 1 H).