Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11]B(O)O.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[CH3:11][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CB(O)O
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(C#N)c(C)n1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A 100 mL round bottom flask equipped with a condenser was charged with 2-Chloro-6-methyl-nicotinonitrile (1 g, 6.55 mmol), MeB(OH)2 (216 mg, 7.22 mmol), K2CO3 (1.36 g, 19.67 mmol), and dioxane (33 mL), followed by Pd(PPh3)4 (758 mg, 0.66 mmol) under argon. The mixture was heated to reflux for 48 hours, and then cooled down to RT. The resulting mixture was concentrated in vacuo, treated with 1N HCl (150 mL), and extracted with EtOAc (100 mL), Et2O (50 mL). The aqueous layer was basified with 50% NaOH until PH=10, and then extracted with EtOAC (100 mL) three times. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5-10% EtOAC/Hexane) to give F2A as a light yellow solid (440 mg). HPLC retention time=0.766 min./condition A, M+=133.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)=[O:4].[H-].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH3:24].Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:7](=[O:18])[CH2:6]1)=[O:4]
Reactant: CCCCI
Reactant: COC(=O)C1CC(=O)Nc2cc(Cl)ccc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CC(C(=O)OC)C(=O)c2ccc(Cl)cc21

Procedure:
The starting material is prepared as follows: The suspension of 6.0 g of 8-chloro-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester in 125 ml of dimethyl formamide is added portion-wise to that of 2.1 g of a 57% mineral oil suspension of sodium hydride in 300 ml of dimethylformamide while stirring under argon. After stirring for 3 hours at room temperature 4.6 g of n-butyl iodide are added dropwise and stirring is continued over night at said temperature. The pH of the mixture is adjusted to 2 with 3N hydrochloric acid and the whole evaporated. The residue is partitioned between water and chloroform, the organic solution separated and the aqueous solution extracted with chloroform. The combined extract is washed with water, dried, evaporated and the residue taken up in diethyl ether. The mixture is treated with charcoal, filtered hot and the filtrate concentrated, to yield the 8-chloro-1-n-butyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, melting at 89°-90°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1ccccn1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: N#N.[CH3:3]C(C)([O-])C.[K+].[F:9][CH:10]1[C:15](=O)[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1.OS([O-])=O.[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:9][CH:10]1[C:15](=[CH2:3])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=S([O-])O
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a suspension of methyltriphenylphosphonium bromide (1.68 g, 4.60 mmol) in dry THF (30 mL) was added potassium tert-butoxide (544 mg, 4.60 mmol) at rt. The reaction mixture was stirred at rt for 30 min. A solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (500 mg, 2.30 mmol) in dry THF (10 mL) was then added and the resulting suspension stirred at rt for 16 h. Aq. 10% NaHSO3 was then added, the mixture extracted with EA. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes-EA, 19:1) to afford the title compound as a colorless oil. LC-MS-conditions 08: tR=0.84 min; [M-CH3+H]+=201.33.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[C@@H:14]([NH2:18])([CH2:16][CH3:17])[CH3:15]>C(O)C>[C@@H:14]([NH:18][C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1)([CH2:16][CH3:17])[CH3:15]
Reactant: CC[C@H](C)N
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Solvent: CCO
Product: CC[C@H](C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 61.6 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) and (S)-(+)-sec-butylamine (0.31 ml, 3.0 mmol) was stirred in 10 ml of abs ethanol for 4 days at 80° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (10 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The initially formed gummy product was crystallized by stirring at 0° C. The precipitate was isolated by filtration, washed with water, and recrystallised from ethyl acetate/methanol followed by drying in vacuo at 30° C. over night to give 181 mg (62%) of the pure title compound; mp 228-230° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ0.88 (t, 3H, CH3), 1.14 (d, 3H, CH3), 1,49 (m, 2H, CH2), 3.68 (m, 1H, CH), 7.08 (s, 1H, H-5), 7.13 (br, 1H, NH), 10.73 (br s, 1H, NH); MS: m/e 293/295 (M+); (C9H12N3Cl1O2S2) calc. C, 36.79; H, 4.12; N, 14.30; found C, 36.9; H, 4.1; N, 14.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:17]3[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=3)[C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:21])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36]>>[NH2:1][C:2]1[C:7]2=[C:8]([C:17]3[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=3)[C:20]([NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:21])[CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cccc(C(=O)Nc4ccccc4)c3)c12
Reactant: CN(C)CC(=O)O
Product: CN(C)CC(=O)N1CCC(c2cc(-c3cccc(C(=O)Nc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 18 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 342 using 3-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-phenylbenzamide and N,N dimethylglycine as starting material, 10 mg (18%) of the desired product was isolated. 1H NMR (400 MHz, DMSO-d6) δ10.24 (s, 1H), 8.02 (s, 1H), 7.96 (m, 2H), 7.80-7.76 (m, 2H), 7.64-7.58 (m, 2H), 7.38-7.36 (m, 2H), 7.11-7.09 (m, 1H), 6.64 (s, 1H), 4.52-4.44 (m, 1H), 4.10-4.00 (m, 1H), 3.50-3.38 (m, 1H), 3.37 (s, 2H), 3.22-3.16 (m, 1H), 2.80-2.70 (m, 1H), 2.36 (s, 6H), 2.10-2.04 (m, 2H), 1.78-1.61 (m, 1H), 1.59-1.30 (m, 1H); LC-MS m/z [M+H]+, 498.4, RT 2.11 min.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:30])[C:28]=1[OH:29])[CH:24]=O.Cl>C(Cl)Cl>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:24][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:26]=[C:27]([CH3:30])[C:28]=1[OH:29]
Reactant: C1CCNC1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CN2CCCC2)cc(C)c1O
Yield: 82.2 %

Procedure:
NaB(OAc)3H (22.1 g, 0.104 mol) was added in portions for 15 min to a mixture of pyrrolidine (8.1 mL, 0.098 mol) and 3,5-dimethyl-4-hydroxybenzaldehyde (12.5 g, 0.083 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (19 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 9 (30 mL) and extracted with chloroform (2×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (14 g, 82%) was obtained as white crystals. LCMS-data: 206.1 and 207.1 (M+H)+ (calculated for C13H19NO 205.1). 1H NMR (400 MHz)-data (DMSO-d6, J, Hz): 7.99 (br s, 1H, OH); 6.80 (s, 2H, ArH); 3.36 (s, 2H, CH2); 2.32-2.41 (m, 4H, CH2CH2CH2CH2); 2.13 (s, 6H, (CH3)2); 1.61-1.70 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1>C(O)C(F)(F)F.ClCCl>[S:6]1[C:2]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[C:5]12
Reactant: COc1ccc(N)cc1
Reactant: Brc1nn2ccnc2s1
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: COc1ccc(Nc2nn3ccnc3s2)cc1
Temperature: 170 °C
Yield: 29.4 %

Procedure:
A mixture of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (1.0 g, 4.90 mmol) and p-anisidine (19.6 mmol, 2.41 g) in trifluoroethanol (12 mL) was heated under microwave irradiation at 170° C. for 1 hour. On cooling, the mixture was diluted with dichloromethane (10 mL) and purified by column chromatography (Biotage™/Flash, silica, methanol: dichloromethane 0.2:9.8 to 1:9). The residue obtained was triturated with diethylether and few drops of methanol to give imidazo[2,1-b][1,3,4]thiadiazol-2-yl-(4-methoxyphenyl)amine as a white solid (355 mg, 29% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:21](O)[CH2:22][OH:23].CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=3)[O:23][CH2:22][CH2:21][O:9]2)=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C2(c3ccc(Cl)cc3)OCCO2)ccc1[N+](=O)[O-]
Yield: 50.4 %

Procedure:
A mixture of (4-chlorophenyl)(3-methoxy-4-nitrophenyl)methanone (40.7 g), 1,2-ethanediol (31.2 ml) and 4-methylbenzene sulfonic acid (5.31 g) in methylbenzene (320 ml) was stirred and refluxed using a Dean-Stark apparatus. The mixture was washed with K2CO3 (10%) and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 22.48 g (50.4%) of 2-(4-chlorophenyl)-2-(3-methoxy-4-nitrophenyl)-1,3-dioxolane (interm. 39).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.Cl[CH2:45][C:46]1[O:50][C:49]([C:51]([O:53][CH3:54])=[O:52])=[CH:48][CH:47]=1.COC1C=CC(CCl)=CC=1>>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[O:50][C:49]([C:51]([O:53][CH3:54])=[O:52])=[CH:48][CH:47]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: COC(=O)c1ccc(CCl)o1
Agent: COc1ccc(CCl)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1

Procedure:
Following the procedure as described in EXAMPLE 7 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and methyl 5-(chloromethyl)-2-furoate to replace 4-methoxybenzyl chloride, methyl 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate was obtained (92%) as a colorless solid: mp 88-92° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.28 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.17 (dd, J=7.2, 0.9 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H), 7.06 (ddd, J=7.8, 7.8, 0.9 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.37 (d, J=3.6 Hz, 1H), 6.24 (s, 1H), 5.12 (d, J=16.5 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.90 (d, J=16.5 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.18 (m, 2H), 4.14-4.10 (m, 2H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.2, 158.9, 155.3, 153.4, 144.8, 144.4, 141.4, 138.4, 132.2, 129.1, 124.1, 123.9, 120.9, 119.1, 111.7, 110.3, 109.1, 99.5, 80.1, 64.6, 64.0, 58.1, 52.1, 37.4; MS (ES+) m/z 433.9 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9][C@H:8]1[CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCn1ccnc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-[2-(imidazol-1-yl)ethyl]-4-hydroxypyrrolidine (9.19 g) in dichloromethane (92 ml) were dropwise added triethylamine (5.79 ml) and methanesulfonyl chloride (3.22 ml) under ice cooling with stirring, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of chloroform and methanol (9:1, V/V) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(imidazol-1-yl)ethyl]-4-(methanesulfonyloxy)pyrrolidine (4.24 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:14][CH2:15]O>S(=O)(=O)(O)O>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(OC)c(Br)c1

Procedure:
A solution of 3-bromo-4-methoxyphenylacetic acid (3.0 g, 12.2 mmol) in EtOH and sulfuric acid was stirred at 100° C. for 2 hours. The mixture was concentrated and partitioned between EtOAc and H2O, and the organic layer was separated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C@:15]3([CH3:31])[CH2:20][C:19](=O)[N:18]([CH3:22])[C:17](=[N:23]C(=O)OC(C)(C)C)[NH:16]3)[CH:12]=[CH:13][CH:14]=2)[C:5]([OH:8])=[CH:6][CH:7]=1.[C:32](O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C@@:15]3([CH2:31][CH3:32])[NH:16][C:17](=[NH:23])[N:18]([CH3:22])[CH2:19][CH2:20]3)[CH:12]=[CH:13][CH:14]=2)[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN1C(=O)C[C@@](C)(c2cccc(-c3cc(Cl)ccc3O)c2)NC1=NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC[C@@]1(c2cccc(-c3cc(Cl)ccc3O)c2)CCN(C)C(=N)N1
Yield: 60 %

Procedure:
(S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH2Cl2 at RT for 30 min. The volatiles were removed in vacuo. The residue was redissolved in acetonitrile (5 mL) and evaporated again to afford 17 mg of the crude product as a yellow solid. The crude product was purified via reverse phase HPLC to provide 10 mg (60%) of (S)-6-(3-(3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1″-one (CF4; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): 611.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m, 3H), 3.68 (brs, 1H), 5.18 (brs, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s, 3H), 2.95(d, J=15.8 Hz, 1H), 1.74 (s, 3H). MS (ESI): MH+=344.1. HPLC (A) Rt=5.07 min.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH3:20])[C:6]=1[C:7]1[S:19][C:10]2[N:11]=[CH:12][N:13]=[C:14](S(C)(=O)=O)[C:9]=2[CH:8]=1.CC1([N:28]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1>>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH3:20])[C:6]=1[C:7]1[S:19][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH2:28])[C:9]=2[CH:8]=1
Reactant: Cn1cnc(I)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Product: Cn1cnc(I)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-(4-iodo-1-methyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 94) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). Beige solid (143 mg, 85%);
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:11]4[S:12][C:8]([CH2:7][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:9][CH:10]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: COCCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCCOC)s4)cc23)CC1
Yield: 9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(methyloxy)propyl]amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 7.6 mg of the title compound (9%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>CC(C)=O>[CH2:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: c1ccc(Cn2ccc3ccccc32)cc1

Procedure:
1-benzylindole was prepared by reaction of the indole with benzyl chloride in the presence of potassium hydroxide in acetone at ambient temperature according to the procedure described in Y. Kikugawa, Y. Miyake Synthesis 1981, 461-462.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@@H:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([CH2:24][OH:25])[O:11][C@H:10]1[O:26][CH2:27][C@H:28]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:66](Cl)(=[O:71])[C:67]([CH3:70])([CH3:69])[CH3:68]>C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@@H:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:12]([CH2:24][O:25][C:66](=[O:71])[C:67]([CH3:70])([CH3:69])[CH3:68])[O:11][C@H:10]1[O:26][CH2:27][C@H:28]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCOC[C@@H](CO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1)OCCCCCCCCCCCCCC
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC[C@@H](CO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1)OCCCCCCCCCCCCCC
Temperature: -5 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Compound 6 (687 mg, 0.831 mmol) was dissolved by addition of pyridine (12 mL). Pivaloyl chloride (130 μl, 1.08 mmol) was added to the solution, and the mixture was stirred at −5° C. for 1 hour. Pivaloyl chloride (130 μl, 1.08 mmol) was further added thereto, and the mixture was stirred at −5° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, then filtered through Celite, and washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:AcOEt=10:1) to obtain Compound 7 (716.6 mg, 94.7%).
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5].OS([O-])(=O)=O.[K+]>C1COCC1>[CH:4]([C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[O:5]
Reactant: CON(C)C(=O)[C@H]1COC(C)(C)N1C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](C=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of LiALH4 (1 M, 20 mL, 20 mmol) was added dropwise to a cold (−15° C.) solution of (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate (12.2 g, 37.9 mmol) in THF (75 mL). The mixture was stirred for 30 min keeping the temperature below 0° C. A saturated solution of KHSO4 (100 mL) was added slowly to the mixture and it was warmed to room temperature. The mixture was filtered and the solvent was removed to dryness. (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate was obtained as a clear oil (9.161 g, 92% yield) after purification by column chromatography (SiO2, using a mixture of hexane/EtOAc). 1H NMR (CDCl3, 400 mHz, ppm); 1.7 (m, 6H), 4.15 (m, 2H), 4.4 (m, 1H), 5.15, (s, 1H), 5.2 (m, 1H), 7.3 (m, 5H), 9.6 (m, 1H).