Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].N1C=CC=CC=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:43][C:21]3[N:22]([CH2:34][C:35]4[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=4[F:42])[C:23](=[O:33])[N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:26])[C:20]=3[C:19]=2[CH2:44][N:45]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH3:46])=[CH:14][CH:13]=1.C(N(CC)CC)C.C[C:62](N(C)C)=[O:63]>O>[CH2:47]([N:45]([CH2:44][C:19]1[C:20]2[C:25](=[O:26])[N:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:33])[N:22]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:21]=2[S:43][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:62]([NH:4][O:3][CH3:2])=[O:63])=[CH:17][CH:16]=1)[CH3:46])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CON
Reactant: CC(=O)N(C)C
Reactant: CN(Cc1ccccc1)Cc1c(-c2ccc(N)cc2)sc2c1c(=O)n(-c1ccccc1)c(=O)n2Cc1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
O-methylhydroxylamine hydrochloride (351 mg, 4.20 mmol) was dissolved in dimethylacetamide (2 ml), pyridine (340 μl, 4.20 mmol) and phenyl chloroformate (phenyl chlorocarbonate)(527 μl, 4.20 mmol) were added thereto successively dropwise, and the mixture was stirred at room temperature for 20 minutes. 6-(4-aminophenyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (500 mg, 0.84 μmol) and triethylamine (1.29 ml, 9.25 mmol) were added thereto, and the mixture was stirred at 50° C. for 18 hours. Water (40 ml) was added thereto, and the mixture was stirred vigorously. The crystals were filtered, and dried under vacuum at 40° C. to give white crystals of 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (0.58 g) quantitatively.
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2cccc(C(F)(F)F)c2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1

Procedure:
Analogous to the procedure described for Example 1A, Step C, 5-[3-hydroxy-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (1.19 g, 3.95 mmol) was protected with tert-butyldimethylsilyl chloride (893 mg, 6.22 mmol). Purification by medium pressure chromatography eluting with EtOAc provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.47–7.32 (m, 4H), 5.73 (m, 1H), 3.86 (m, 1H), 3.59 (m, 1H), 2.75 (m, 2H), 2.35–2.20 (m, 3H), 1.70–1.40 (m, 5H), 0.81 (s, 9H), −0.05 (d, 3H), −0.3 (d, 3H); MS 416.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:38]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].I[CH2:10][C:11](=[O:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11]([CH3:12])=[O:13]
Reactant: CC(=O)CI
Reactant: Nc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CNc1ccccc1Cl
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a solution of chloroacetone (8.0 mL, 0.100 mol) in 100 mL acetone was added KI (33.20 g, 0.200 mol). The suspension was stirred under argon at rt for 24 h. Acetone was evaporated under reduced pressure. The residue was extracted with ether. The ethereal solution was concentrated under reduced pressure to yield iodoacetone as a brown liquid (18.00 g, 98%). A mixture of 2-chloroaniline (8.95 mL, 0.085 mol), iodoacetone (18.00 g, 0.098 mol), K2CO3 (12.35 g, 0.090 mol) and DMF (200 mL) was heated under argon for 48 h. The mixture was cooled to rt, and water was added. The mixture was extracted with ether (3×300 mL). The combined organic phases were washed with water (2×300 mL), dried over Na2SO4, and evaporated. The crude product was purified on silica gel, eluting with 1:5 EtOAc/hexanes to yield the product as a brown liquid (14.07 g, 77%), which was used in procedures similar to Examples 16 and 17.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:26]3[C:31]4[S:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[C:30]=4[CH:29]=[CH:28][CH:27]=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3.C[O:40][B:41](OC)[O:42]C.Cl>O1CCCC1>[CH:29]1[C:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:26]([N:17]2[C:16]3[CH:15]=[CH:14][C:13]([B:41]([OH:42])[OH:40])=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:27][CH:28]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
An excess of 1.6M n-BuLi in hexane (14 mL, 22.3 mmol) was added to a solution of 3-bromo-9-(diberizo[b,d]thiophen-4-yl)-9H-carbazole (8.7 g, 20.3 mmol) in 100 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C. Trimethylborate (2.8 g, 26.4 mmol) was added dropwise; the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (50 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum, and the residue was crystallized from n-hexane to give the 9-(dibenzo[b,d]thiophen-4-yl)-9H-carbazol-3-ylboronic acid 4.7 g (59%)
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@@H:10]([CH2:19][N:20]([C@@H:28]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9]2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:40][I:41]>C(#N)C>[I-:41].[C:23]([O:22][C:21]([N:20]([CH2:19][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][N:8]([C:6]([N:1]2[CH:5]=[CH:4][N+:3]([CH3:40])=[CH:2]2)=[O:7])[CH2:9]1)[C@@H:28]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[CH3:29])=[O:27])([CH3:25])([CH3:24])[CH3:26]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)n2ccnc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CI
Solvent: CC#N
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)n2cc[n+](C)c2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 40 ml acetonitrile solution of 1.234 g of tert-butyl {[(3R,4S)-1-(1H-imidazol-1-ylcarbonyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was mixed with 0.60 ml of methyl iodide and stirred overnight at room temperature. By evaporating the reaction solution under a reduced pressure, 1.966 g of 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}-3-methyl-1H-imidazol-3-ium iodide was obtained as a pale yellow solid . . . EP: 539.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:11][NH:10][CH:9]=[N:8][CH2:7]1)=[O:5].N12CCCN=C1CCCCC2.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:8]2[CH2:7][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:11][N:10]=[CH:9]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CN=CNC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
1,4,5,6-Tetrahydro-5-methoxycarbonylpyrimidine hydrochloride (I.49 g, 8.3 mmol), 1,8 diazabicyclo [5.4.0] undec-7ene, (hereinafter diazabicycloundecene and/or DBU), (2.5 mL, 16.6 mmol), and tritylchloride (2.32 g, 8.3 mmol) were suspended in anhydrous DMF (20 ml) with stirring under nitrogen at room temperature. After 18 hours stirring the suspension was evaporated in vacuo and the residue chromatographed (silica, chloroform/methanol, 9:1) to yield 2.28 g (rf=0.15, 71%) white crystalline solid identified by 300 MHz nmr and ms m/z=384.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.C([N:36]1[CH:45]([CH:46]=O)[CH2:44][CH:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH2:42]2)[CH2:37]1)(OC(C)(C)C)=O.S([O-])([O-])(=O)=[O:49].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:49])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:46][C@@H:45]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37][NH:36]2)[CH2:6]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC2=CC=CCC2CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@]1(C(=O)O)CN(C[C@@H]2Cc3ccccc3CN2)C[C@@H]1CCCB(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-BOC-tetrahydroisoquinoline-3-carboxaldehyde (0.196 g, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at room temperature for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)pyrrolidine-3-caboxylic acid (146 mg, 62%) as a white solid. NMR (D2O) δ 7.10-7.30 (m, 4 H), 4.39 (br s, 22 H), 3.85-4.10 (m, 3 H), 3.60-3.80 (m, 3 H), 3.20-3.50 (m, 2 H), 2.90-3.10 (m, 1 H), 2.62 (m, 1 H), 1.60 (m, 1 H), 1.15-1.30 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 362.4; MS (m−H2O+1): 344.0.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:15]>>[I:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH:13]=[CH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: O=Cc1ccc2ccccc2c1
Product: O=C(C=Cc1ccc2ccccc2c1)c1ccc(I)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 2-naphthaldehyde and 4-iodoacetophenone, 1-(4-iodophenyl)-3-(2-naphthalenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([O:70][C:71](=[O:89])[NH:72]/[C:73](/[NH:85][CH2:86][CH:87]=[CH2:88])=[N:74]\[C:75](=[O:84])[O:76][CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:77]([O:76][C:75]([NH:74][C:73]([NH:85][CH2:86]/[CH:87]=[CH:88]/[C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C:44]2[C:43]([CH3:54])=[CH:42][C:41]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:40]([C@@H:10]3[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C@@H:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:9]3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:45]=2)=[CH:48][CH:49]=1)=[N:72][C:71]([O:70][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:89])=[O:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: C=CCN/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Yield: 45.4 %

Procedure:
To an acetonitrile solution (3 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-methylphenyl]-D-glucitol (271 mg, 0.305 mmol) were added dibenzyl[(Z)-(allylamino)methylylidene]biscarbamate (335 mg, 0.914 mmol), palladium(II) acetate (18 mg, 0.0791 mmol), tri-O-tolylphosphine (61 mg, 0.201 mmol) and triethylamine (154 mg, 1.52 mmol), and reacted at 120° C. for 20 minutes with microwave manufactured by Biotage. The reaction solution was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (163 mg, 46%) as a pale yellow amorphous compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[O:17][CH3:18])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([C:16]=1[O:17][CH3:18])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC)c2ccccc2n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 4.6 g (0.096 mole) of 50% sodium hydride/mineral oil in 100 ml of N,N-dimethylformamide under a nitrogen atmosphere was cooled in an ice bath. To the stirred mixture was added over 45 minutes, a solution of 19.5 g (0.089 mole) of 3-methoxy-1H-indole-2-carboxylic acid ethyl ester [A. Galun, A. Markus, and A. Kampf, J. Heterocyclic Chem., 16, 221 (1979)] in 50 ml of N,N-dimethylformamide. The mixture was stirred for an additional 30 minutes, and a solution of 11.6 ml (16.7 g; 0.098 mole) of benzyl bromide in 10 ml of N,N-dimethylformamide was added over 15 minutes. The ice bath was removed, the mixture was stirred for an additional 16 hours, and then added to 800 g of ice water. The crude ester intermediate was removed by extracting with dichloromethane (4×250 ml). The combined organic layers were back-washed with brine (3×500 ml), dried (anhydrous sodium sulfate), and evaporated to yield a crude residue of 3-methoxy-1(phenylmethyl)-1H-indole-2-carboxylic acid ethyl ester, plus a small amount of N,N-dimethylformamide.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO.C(Cl)Cl>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(OCCN(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
0.68 g (2.27 mmol) of methyl 4-[4-(2-dimethylaminoethoxy)phenyl]benzoate was dissolved in 18 ml of methanol-methylene chloride (5:1 (v/v)). 3.4 ml of a 1N sodium hydroxide aqueous solution was added thereto and the mixture was refluxed under heating for 5 hours. After cooling to room temperature, 3.4 ml of 1N hydrochloric acid was added and stirred. The precipitate thus formed was collected by filtration, washed, and dried to obtain 0.54 g (1.89 mmol) of 4-[4-(2-dimethylaminoethoxy)phenyl]benzoic acid as faint yellowish white powder. ##STR22## Its spectroscopic data are as follows:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH:11]=2)[C:6](=[O:22])[N:5]2[C:23]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[NH:24][C:25](=[O:26])[C:4]=12)=[O:2]>CO.O1CCCC1.[BH4-].[Na+].O>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[CH:11]=2)[C:6](=[O:22])[N:5]2[C:23]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[NH:24][C:25](=[O:26])[C:4]=12
Reactant: O=Cc1cc(Nc2cc(NC(=O)C3CC3)ncn2)c(=O)n2c1C(=O)NC21CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NC2(CCCCC2)n2c1c(CO)cc(Nc1cc(NC(=O)C3CC3)ncn1)c2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(6-((8′-formyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (1.2 g, 2.85 mmol) in methanol/tetrahydrofuran (1:2, 30 mL), sodium borohydride was added portion wise at 0° C. The reaction mass was stirred at 0° C. for 2 h. After completion, the reaction mixture was diluted with water (100 mL) and the mixture was extracted with 10% methanol in dichloromethane (2×50 mL). The organics were then separated and dried (magnesium sulfate) and concentrated to dryness under vacuum to afford N-(6-((8′-(hydroxymethyl)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (5) as brown solid. Yield: 0.7 g, 62%; MS (ESI) m/z 423.43 [M−1]−; 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 10.24-10.18 (m, 1H), 8.71-8.62 (m, 1H), 8.56-8.52 (m, 1H), 7.84 (s, 1H), 6.13-5.33 (m, 1H), 4.47-4.33 (m, 3H), 3.16-2.84 (m, 4H), 2.01-1.86 (m, 2H), 1.72-1.66 (m, 5H), 1.43-1.40 (m, 2H), 1.34-1.16 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH:11][CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1.[CH2:24](N(CC)CC)C>C(O)(C)C>[CH3:24][C:10]1[C:3]2[C:2]([O:11][CH2:12][C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: Clc1ncnc2sccc12
Reactant: CCN(CC)CC
Reactant: OCc1cc(-c2ccccc2)no1
Solvent: CC(C)O
Product: Cc1csc2ncnc(OCc3cc(-c4ccccc4)no3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.184 g (1 mmol) of 4-chloro-thieno[2,3-d]pyrimidine was dissolved in 5 ml of dry isopropanol. A solution of 0.175 g (1 mmol) of 5-hydroxymethyl-3-phenyl-isoxazole in 5 ml isopropanol was slowly added dropwise into the reaction system, followed by the addition of 0.101 g (1 mmol) freshly distilled triethylamine. The system was stirred at room temperature for 30 min and then was reacted at 60. After the completion of the reaction monitored by TLC, the reaction solution was concentrated under vacuum. The residue was directly separated on (V(petroleum ether):V(ethyl acetate)=9:1-4:1) to give the target compound of 5-methyl-4-((3-phenyl-isoxazol-5-yl)-methoxy-)-thieno[2,3-d]pyrimidine (named S-1 in the following Table). The other compounds were synthesized according to the synthetic process of 5-methyl-4-((3-phenyl-isoxazol-5-yl)-methoxy-)-thieno[2,3-d]pyrimidine. Their structures were determined by analytical methods of IR, 1H NMR, ESI-MS, etc. The physical constants and spectral data of preferred compounds were illustrated in the form of table.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:25][CH2:26][CH3:27])[CH3:24].[ClH:28]>CN(C=O)C.CO>[ClH:28].[O:25]([C:26]1[CH:2]=[CH:3][CH:4]=[CH:5][C:27]=1/[CH:12]=[CH:13]\[CH2:14][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:3][CH2:2]1)[C:23]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:24]=1
Reactant: CCOCC
Reactant: O=C1c2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN1C1CCN(C/C=C\c2ccccc2Oc2ccccc2)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of Part E compound (600 mg, 2.45 mmol) in DMF (20 mL) was added Example 2 Part A compound (2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-1-one) (530 mg, 2.45 mmol) followed by anhydrous potassium carbonate (372 mg, 2.69 mmol). The reaction was stirred at 55° C. overnight. The reaction was cooled to RT. Ethyl ether (200 mL) was added to dilute the reaction, and the organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over MgSO4. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g of silica gel, loaded and eluted with 2% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting oil was dissolved in methanol (2 mL) and HCl in ethyl ether solution (1.0M, 3.0 mL, 3.0 mmol) was added. The HCl salt precipitated from the solution. The salt was filtered and dried at 60° C. under vacuum to give title compound (490 mg, 80%) as a white solid.