Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:9]=3[S:8](=[O:21])(=[O:20])[C:7]=2[CH:22]=1)#[N:2].Cl.[OH-].[Na+]>O1CCCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:9]2[S:8](=[O:21])(=[O:20])[C:7]3[CH:22]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=1
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(N)cc1C=C2

Procedure:
875 Mg. 3-cyano-8-nitrodibenzo[b,f]thiepin-5,5-dioxide are dissolved in 105 cc. tetrahydrofuran. 15 CC. concentrated hydrochloric acid is added, followed by 3.8 g. stannous chloride dihydrate and the mixture is stirred for 24 hours. A solution of 20% sodium hydroxide is added, the mixture is shaken and the organic layer separated; the aqueous phase extracted once with ethyl acetate. The combined organic extracts are dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel to yield 464 mg. (58%) pure amino compound, m.p. 321°-324° C.
Reaction SMILES: [F:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.[Cl:7][C:8]1[CH:9]=[C:10]([N:15]2[C:19](=[O:20])[CH:18]([CH3:21])[NH:17][C:16]2=[O:22])[CH:11]=[CH:12][C:13]=1[Cl:14].C(N(CC)CC)C>C(OC(=O)C)C>[Cl:5][C:2]([Cl:6])([F:1])[S:3][N:17]1[CH:18]([CH3:21])[C:19](=[O:20])[N:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[C:16]1=[O:22]
Reactant: FC(Cl)(Cl)SCl
Reactant: CC1NC(=O)N(c2ccc(Cl)c(Cl)c2)C1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1C(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)N1SC(F)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.4 g of fluorodichloromethanesulphenyl chloride is added dropwise at 0° C, with thorough stirring, to 25.9 g of 3-(3',4'-dichlorophenyl)-5-methyl-imidazolidine-2,4-dione in 500 ml of acetic acid ethyl ester, and after 2 hours an addition is made dropwise, likewise at 0° C. of 12.1 g of triethylamine in 100 ml of acetic acid ethyl ester. After the whole has been stirred for 3 hours at room temperature, the triethylamine hydrochloride is filtered off; the solvent is evaporated off from the filtrate and the residue is recrystallised in methanol. Compound No. 2 melts at 138° - 140° C after recrystallisation.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[CH3:6][O:7][CH:8]([O:18]C)[CH:9]([CH:13](OC)OC)[C:10]([O-])=O>CN(C)C=O>[CH3:6][O:7][C:8]([C:9]1[CH:10]=[N:4][C:3]([NH2:5])=[N:2][CH:13]=1)=[O:18]
Reactant: N=C(N)N
Reactant: COC(OC)C(C(=O)[O-])C(OC)OC
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N)nc1
Temperature: 140 °C

Procedure:
To a stirred solution of 4.30 g guanidine hydrochloride in 50.00 g dimethyl formamide, 10.00 g 3,3-dimethoxy-2-dimethoxymethyl-propionate were added. The resulting clear solution was heated to 100° C. for 2 hours and to 140° C. for an additional 20 hours. After cooling to 60° C., the solvent was completely removed in vacuo and the resulting light brown residue thoroughly extracted with boiling tetrahydrofurane. After distilling off the majority of the solvent, the crystalline product was isolated by suction filtration and subsequent drying in vacuo. A total of 4.34 g (63% of theory based on 3,3-dimethoxy-2-dimethoxymethyl-propionate) of methyl-2-amino-pyrimidine-5-carboxylate could be isolated in this way. Identification of the product was based on 1H-NMR-, 13C- and IR-spectra.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:28]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:28][CH2:27][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:18]1
Reactant: CC(I)C1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CCC4CCCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 35 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and (1-iodoethyl)cyclohexane.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[C:8]=1[C:9]([OH:11])=[O:10].[CH3:17]O>C(OCC)(=O)C>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[C:8]=1[C:9]([O:11][CH3:17])=[O:10]
Reactant: CO
Reactant: O=C(O)c1c(F)cccc1I
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)cccc1I

Procedure:
Concentrated sulphuric acid (0.5 ml) was added to a solution of 2-fluoro-6-iodobenzoic acid (1.03 g) in methanol (35 ml). After stirring at reflux for 5 days, with two further amounts of conc. sulphuric acid (1 ml) being added after 1 and 2 days, the solution was allowed to cool. The reaction mixture was diluted with ethyl acetate (200 ml) before being washed with water (2×80 ml), 8% aqueous sodium bicarbonate (2×100 ml), dried and concentrated in vacuo. Purification by chromatography eluting with System A (1:3) afforded the title compound (0.72 g) as an orange oil.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[C:18]([CH:19]=[O:20])=[CH:17][NH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:13][C:14]1[C:18]([CH:19]=[O:20])=[CH:17][N:16]([C:2]2[C:7]([CH:8]3[CH2:12][CH2:11][CH2:10][O:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)[N:15]=1
Reactant: Cc1n[nH]cc1C=O
Reactant: Fc1ncccc1C1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ncccc2C2CCCO2)cc1C=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
To a screw-cap test tube containing 2-fluoro-3-(tetrahydrofuran-2-yl)pyridine (148 mg, 0.88 mmol) in dimethylformamide (2.2 mL) are added 3-methyl-1H-pyrazole-4-carbaldehyde (81 mg, 0.74 mmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and stirred in a preheated oil bath at 110° C. for 18 h with the aid of a magnetic stirrer. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The resulting residue is purified by silica gel using normal phase Isco chromatography eluting with hexane: acetone (gradient from 5 to 20% in acetone) to give 116 mg of the title compound. MS (m/z): 258 (M+1).
Reaction SMILES: OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([N:51]3[C:55]4=[N:56][CH:57]=[CH:58][CH:59]=[C:54]4[CH:53]=[CH:52]3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:60][CH2:61][N:62]([CH:65]3[CH2:68][O:67][CH2:66]3)[C:63](=[O:64])[C:39]=12)C1C=CC=CC=1>>[OH:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([N:51]3[C:55]4=[N:56][CH:57]=[CH:58][CH:59]=[C:54]4[CH:53]=[CH:52]3)[CH2:47][CH2:48][CH2:49][CH2:50]2)[N:40]2[CH2:60][CH2:61][N:62]([CH:65]3[CH2:66][O:67][CH2:68]3)[C:63](=[O:64])[C:39]=12
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1COC1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(O)c2C1=O
Product: O=C1c2c(O)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1COC1

Procedure:
9-Hydroxy-2-oxetan-3-yl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (424) was prepared following the same method as described for 9-hydroxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (408) from 9-Benzyloxy-2-oxetan-3-yl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (423) (13 mg, 0.03 mmol) and was obtained as an off-white solid (8 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]=[N+]=[N-])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(S)CCS>CO>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1
Agent: SCCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CN)cc1-c1ccccc1

Procedure:
To the resultant compound from Example 18A in methanol is added triethylamine (3.0 equivalent) and propane 1,3-dithiol (3.0 equivalents). After the reaction is judged complete by TLC analysis, the mixture is filtered and evaporated. Chromatography of the residue on silica gel provides the title product.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:58][CH2:59][C@@H:60]1[CH2:64][CH2:63][CH2:62][N:61]1[C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66].O.[C:73]([OH:79])([C:75]([F:78])([F:77])[F:76])=[O:74]>CN(C=O)C>[F:76][C:75]([F:78])([F:77])[C:73]([OH:79])=[O:74].[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([NH:58][CH2:59][C@@H:60]3[CH2:64][CH2:63][CH2:62][N:61]3[C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])=[O:19])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NC[C@@H]3CCCN3C(=O)OC(C)(C)C)n2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
75 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 21A, 0.23 mmol, 1 equivalent), 90 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 0.24 mmol, 1.05 equivalents) and 88 mg of N,N-diisopropylethylamine (0.12 ml, 0.68 mmol, 3 equivalents) were initially charged in 1.4 ml of DMF and stirred at RT for 20 min. 50 mg (0.25 mmol, 1.1 equivalents) of tert-butyl (2S)-2-(aminomethyl)pyrrolidine-1-carboxylate were then added, and the mixture was stirred at RT overnight. The reaction solution was then diluted with water/TFA and purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 143 mg (99% of theory; purity 98%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].CCCCCC.C([Li])CCC.[Si:21]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[O:46])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C.C(OCC)C.O1CCCC1>[Si:21]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9])[OH:46])([C:34]([CH3:36])([CH3:37])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CC(C)(C)[Si](OCCCCCCC=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCCCCCC(O)c1cc(F)ccc1F)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A tetrahydrofuran (40 ml) solution of 1-bromo-2,5-difluorobenzene (1.21 ml, 10.7 mmol) was stirred at −78° C., followed by the addition of a hexane solution (8.50 ml, 13.4 mmol) of n-butyl lithium. The reaction mixture was added to a tetrahydrofuran (20 ml) solution of 7-(t-butyldiphenylsilyloxy)heptanal (3.28 g, 8.90 mmol) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. After the temperature of the reaction mixture was elevated to room temperature, diethyl ether was added thereto. The mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure, whereby the title compound (3.88 g, 8.04 mmol, 90%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])C(O)=O)=[CH:4][CH:3]=1.B.C1C[O:17][CH2:16]C1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:12][CH2:16][OH:17])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: B
Product: OCCCc1ccc(F)cc1

Procedure:
para-Fluorophenylpropionic acid (5.15 g, 31.0 mmol, 1 eq.) was dissolved in THF (150 mL). To this solution a 1.0 M solution of borane in THF was added dropwise (caution—exothermic) at 25° C. under N2. The mixture was refluxed overnight. The reaction was quenched with excess 1N HCl and extracted 3 times with EtOAc. The organic layers were dried (MgSO4), and stripped to yield 5.67 g of a pink oil. Evaporative distillation at 0.05 mmHg and 193-260° C. yielded 2.32 g of product as a clear colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:23])=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 4-nitrophenyl isocyanate. m/z (ES+) 309 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([OH:19])=O)[CH2:11]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:19])[CH2:11]2)[CH:3]=1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C)n1
Reactant: NC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 0 °C
Yield: 108.7 %

Procedure:
To a suspension of (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (3.05 g, 10.71 mmol) in CH2Cl2 (50 mL) at room temperature was added Hunig's base (2.70 mL, 15.43 mmol, 1.3 equiv) and cyclohexylamine (1.60 mL, 14.2 mmol, 1.2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (4.96 g, 13.1 mmol, 1.1 equiv) in one portion, and the resulting suspension was stirred in the ice bath for 30 minutes. LCMS showed conversion complete. The mixture was diluted with CH2Cl2 (50 mL) and filtered through celite. The filtrate was washed water (2×25 mL) and then brine. The organic was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 50% EtOAc in CHCl3 afforded the title compound (4.26 g) as a foam. LC-MS (ES) m/z=366 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[Sn](CCCC)(CCCC)(Cl)Cl.C1([SiH3])C=CC=CC=1>C1COCC1>[N:15]1([C:18]2[CH:19]=[CH:20][C:21]([NH:22][CH2:1][C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
A suspension of 4-formylbenzoic acid (2.53 g; 16.8 mmol; 1 eq), 4-morpholinoaniline (3 g; 16.8 mmol; 1 eq) and Bu2SnCl2 (510 mg; 1.68 mmol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH3 (3.31 ml; 16.8 mmol; 1 eq) at room temperature for 12 h. The reaction was filtered and the solid product was washed with MeOH. The yield of the reaction was 5.25 g (99%). LRMS: calc 312.37. found: 313.2.
Reaction SMILES: [C:1]1([CH3:48])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH:12]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:39]CC4C=CC=CC=4)=[O:38])[CH:32]=3)=[O:29])[C:11]2=[O:47])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>C(O)C.[C].[Pd]>[C:1]1([CH3:48])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:13][CH:12]([NH:27][C:28](=[O:29])[NH:30][C:31]3[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:37]([OH:39])=[O:38])[C:11]2=[O:47])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)CN(C(=O)C(C)(C)C)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
10% Palladium carbon (200 mg) was added to a solution of 1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea (1.4 g) obtained from Step 3 in ethanol (50 ml), stirred for 8 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure, to thereby obtain 1.04 g of (+)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoic acid (Yield: 86%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=NC=N1>C(#N)C>[C:15]([CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1nc[nH]n1
Solvent: CC#N
Product: O=C1CCCC(=O)C1C(=O)c1ccccc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A mixture of 1,3-Cyclohexanedione (2.31 g), potassium carbonate (1.5 g) and acetonitrile (20 ml) were stirred at 35° C. for 3 hrs. To the resulting suspension was added benzoylchloride (1.5 g) over a few minutes and the mixture was stirred for 30 minutes. Potassium carbonate (2 g) and 1,2,4-triazole (0.035 g) were then added and the mixture was stirred at 35° C. for 16 hrs. After this time the reaction mixture was evaporated under reduced pressure, the mixture dissolved in water and acidified with HCl to precipitate the product. Extraction into chloroform and evaporation gave a 90% yield of 2-benzoyl-1,3-cyclohexanedione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C[Mg+].[Br-].[Cl:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1.CCOC(C)=O>[Cl:31][CH2:32][C:33]([N:14]([C:12]1[C:11]([C:19]#[N:20])=[CH:10][C:9]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:13]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:34]
Reactant: CC(C)CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: O=C(Cl)CCl
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)CCl)c1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reaction time: 0.08 h

Procedure:
To the product of Step A EXAMPLE 27 (300 mg) in THF (5.0 mL) was added MeMgBr (0.92 mL, 1.4 M solution in toluene/THF 3:1) at 0° C. The reaction stirred for 5 minutes before adding chloroacetyl chloride (0.08 mL). The reaction stirred about 7 hours and was diluted with EtOAc, washed with 2 M aqueous HCl and brine. The dried solution (Na2SO4) was concentrated and purified via flash chromatography on silica gel gradient eluted with 0-15% EtOAc in hexane affording the title compound. HPLC/MS: 471.9 (M+1), 473.9 (M+3); Rt=4.32 min.
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=O)[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1.B.Cl.[OH-].[Na+]>O1CCCC1.O.CO>[CH3:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH3:15])[CH2:7][C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)N(C)C(=O)c1cscc1N2
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C)N(C)Cc1cscc1N2
Reaction time: 1 h

Procedure:
To a slurry of 3.88 g. of 4,9-dihydro-6,7,9-trimethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of tetrahydrofuran, cooled in an ice bath and stirred under argon is added 60 ml. of 1 M borane in tetrahydrofuran, dropwise over 15 minutes. The mixture is stirred for one hour at room temperature, refluxed for 18 hours, cooled in an ice bath and decomposed by the addition of 30 ml. of 6 N hydrochloric acid. The mixture is stirred for one hour, 30 ml. of 10 N sodium hydroxide is added, stirring is continued for one hour and the tetrahydrofuran is evaporated. The remaining aqueous layer is filtered giving blue tinted crystals. These crystals are combined with 125 ml. of absolute methanol and saturated with gaseous hydrogen chloride. A 25 ml. portion of water is added and the mixture is heated on a steam bath until solution is complete. The methanol is evaporated in vacuo, 150 ml. of water is added and the solution is made basic with 10 N sodium hydroxide. The solution is extracted with methylene chloride and the extract is dried over magnesium sulfate and evaporated giving the desired product as blue crystals, mp. 121°-125° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([NH:14]C(OCC2C=CC=CC=2)=O)[CH:11]=[CH:10][C:9]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=1)(=[O:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=1)(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(N)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 5-benzyloxycarbonylamino-2-(4-ethyl-benzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.35 g) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder (0.07 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/3-dichloromethane/ethyl acetate=1/1) to give 5-amino-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.19 g).