Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]#[N:26])[CH2:21][CH2:20]4)[CH2:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:28][NH:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=N>>[CH:32]1([C:30]2[N:26]=[C:25]([N:22]3[CH2:21][CH2:20][CH:19]([CH:17]4[CH2:16][C:15]5[CH:27]=[C:11]([C:8]6[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=6)[CH:12]=[CH:13][C:14]=5[O:18]4)[CH2:24][CH2:23]3)[O:28][N:29]=2)[CH2:34][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C#N)CC2)O3)cc1
Reactant: N=C(NO)C1CC1
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(c4nc(C5CC5)no4)CC2)O3)cc1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carbonitrile and N-hydroxy-cyclopropanecarboxamidine following a procedure analogous to that described in Example 2. LC (method 2): tR=1.08 min; Mass spectrum (ESI+): m/z=466 [M+H]+.
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:20]=[C:19](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc(/C=C/c2ccccc2)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
20 mg of 5% palladium-carbon was added to a mixed solution of 1 mL of methanol and 2 mL of ethyl acetate containing 0.10 g of 2-(benzamido)-4-((E)-2-phenylvinyl)benzoic acid and stirred under hydrogen atmosphere at room temperature for 5 hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 69 mg of 2-(benzamido)-4-phenethylbenzoic acid as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5](Cl)[C:6]([CH3:8])=O)[CH3:2].[CH:11]([NH2:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4]([C:5]1[O:12][CH:11]=[N:13][C:6]=1[CH3:8])=[O:10])[CH3:2]
Reactant: NC=O
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ocnc1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 39.8 %

Procedure:
To ethyl-2-chloroacetoacetate(5.6 g) was added formamide(4.6 g). The reaction mixture was stirred at 120° C. for 12 hours, cooled to 0° C. and aqueous potassium carbonate was added thereto. The mixture was extracted with benzene, dried with anhydrous magnesium sulfate, and concentrated in vacuo to obtain the target product(2.1 g).
Reaction SMILES: C(N(CC)CC)C.[Br-].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:16]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:15][C:14]2=[O:41].[N:42]1[CH:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=1>C(Cl)Cl>[CH3:21][O:20][C:19]1[CH:18]=[C:17]2[C:13](=[CH:12][C:11]=1[O:10][CH3:9])[C:14](=[O:41])[O:15][C:16]2=[CH:48][C:45]1[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=1
Reactant: O=Cc1ccncc1
Reactant: COc1cc2c(cc1OC)C([P+](c1ccccc1)(c1ccccc1)c1ccccc1)OC2=O
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=Cc1ccncc1)OC2=O
Yield: 60.9 %

Procedure:
Triethylamine (20 ml, 145 mmoles) was added dropwise to a suspension of (5,6-dimethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenylphosphonium bromide (78 g, 145 mmoles), obtained as described in example 12, and 4-pyridincarboxaldehyde (13.0 ml, 145 mmoles) in methylene chloride (1 l), at room temperature, under stirring. After 1.5 hours the mixture was filtered and evaporated and the residue was treated with boiling ethanol, cooled and filtered. The mother liquors were chromatographed (eluent: methylene chloride then with 1% methanol) and the residue was brought to dryness and joined to the above filtrate to give 25 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)=[O:4].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11](=[NH:12])[NH:14][OH:15])=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C#N)nc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(C(=N)NO)nc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of 2-cyano-pyrimidine-5-carboxylic acid methyl ester 3 (1 g, 6.13 mmol) in MeOH (20 mL) at room temperature is added hydroxylamine hydrochloride (0.64 g, 9.2 mmol) and sodium acetate (0.76 g, 9.2 mmol). The resulting mixture is heated to reflux for 2 hours. The mixture is cooled to room temperature and concentrated in vacuo. Water (30 mL) is added to the residue, and the solid is filtered, and washed with water twice. The solid is dried in vacuum oven overnight to afford 2-(N-hydroxycarbamimidoyl)-pyrimidine-5-carboxylic acid methyl ester (1.09 g, 91%) as a solid. MS: 197 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[C:18](SC)[S:19][CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:6]=[CH:7][CH:8]=1.O.[NH2:24][NH2:25]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:24][NH:25][C:18]=2[S:19][CH3:20])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C(=O)c2ccccc2)=C(SC)SC)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2c(-c3ccccc3)n[nH]c2SC)c1

Procedure:
To a solution of 2-(3-methoxyphenyl)-3,3-bis(methylthio)-1-phenylprop-2-en-1-one in EtOH (100 mL) was added hydrazine hydrate (5.36 mL, 110 mmol). The reaction mixture was refluxed overnight, additional hydrazine hydrate (1.00 mL, 20.6 mmol) was added, and the mixture was refluxed until the reaction was complete. The mixture was concentrated under reduced pressure, washed with H2O and extracted with CH2Cl2. The combined organic layers were washed with H2O, brine, dried over MgSO4 and concentrated to give the title compound (6.67 g). LCMS m/z=397 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:12]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Product: Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Yield: 77.8 %

Procedure:
Using 3′,4′-dichloroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.CN1CCOCC1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:2]2[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: COC(=O)C1CNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1CN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of methyl azetidine-3-carboxylate hydrochloride (1.236 g, 8.15 mmol) and N-methylmorpholine (2.338 ml, 21.26 mmol) in dimethylformamide (10 mL) was treated with a solution of 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) in dimethylformamide (7 mL) and the reaction was allowed to stir at room temperature for 60 hours. Water (50 mL) was added and the resulting suspension was stirred 10 minutes and filtered. The collected solid was washed with water and dried under vacuum. Flash chromatography of the collected solid provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([NH:21][C:22]([C@@H:24](/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:53])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C@@:25]([OH:36])([CH2:33][CH2:34][OH:35])[C:26]([O:28][C:29](C)(C)C)=[O:27])=[O:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]([NH:21][C:22]([C@@H:24](/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:53])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C@@:25]([OH:36])([CH2:33][CH2:34][OH:35])[C:26]([O:28][CH3:29])=[O:27])=[O:23])[C:6]([O:5][CH3:1])=[O:7])=[CH:15][CH:14]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC)C(=O)OC)cc1
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of No. 4984967, tert-butyl (E)-(2S,3S)-3-[(S)-1-tert-butoxycarbonyl-2-(4-but-2-ynyloxy-phenyl)-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (112 mg, 0.152 mmol) and dichloromethane (1.3 mL) was cooled to 4° C., and acetic anhydride (35.8 μL, 0.379 mmol), triethylamine (23.3 μL, 0.167 mmol), and DMAP (1.9 mg, 0.02 mmol) were added. After stirring for 2 hours, the consumption of the starting materials was confirmed by LCMS. The solvent was distilled off under reduced pressure. Formic acid (10 mL) was added and the mixture was stirred at room temperature for 15 hours. Formic acid was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC and then freeze-dried to obtain the title compound (46 mg, 45% yield, colorless oil).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].O=[CH:14][C:15](=[CH2:17])[CH3:16]>>[CH3:9][O:8][C:5]1[CH:6]=[C:7]2[C:2](=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)[N:1]=[CH:16][C:15]([CH3:17])=[CH:14]2
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: C=C(C)C=O
Product: COc1cc([N+](=O)[O-])c2ncc(C)cc2c1
Yield: 50 %

Procedure:
4-Amino-3-nitroanisole was subjected to a Skraup reaction with 90% methacrolein at 110° to afford a 50% yield of 6-methoxy-3-methyl-8-nitroquinoline. The compound crystallized from ethyl acetate as a yellow solid, mp 173°-175°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@H:12]([CH2:21][OH:22])[CH2:11][CH2:10]4)[C@H:7]([CH3:23])[CH2:6][C:5]=2[CH:4]=1.C([O-])(=O)C.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@H:12]([CH:21]=[O:22])[CH2:11][CH2:10]4)[C@H:7]([CH3:23])[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)[C@H](CO)CC[C@H]12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)[C@H](C=O)CC[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
—Pyridinium chlorochromate (10.1 g) was added to a solution of (7α,14β,17α)-3-methoxy-7-methylestra-1,3,5(10)-triene-17-methanol (Example 4, step iv; 5.90 g) in dichloromethane (295 ml) containing sodium acetate (8.85 g) and silica (17.7 g). After 3 h stirring at room temperature the reaction mixture was filtered over dicalite and the filtrate was concentrated under reduced pressure. Column chromatography afforded (7α,14β,17α)-3-methoxy-7-methylestra-1,3,5(10)-triene-17-carboxaldehyde (4.16 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:25]([NH:27][C@H:28]([C:41]([OH:43])=[O:42])[CH2:29][CH2:30][C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:26])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[NH:52]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C@H:53]([C:64]([O:66]N1C(=O)CCC1=O)=O)[C@@H:54]([CH3:63])[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.CCN(CC)CC>C1COCC1.CN(C=O)C.CS(C)=O>[NH:52]([C:74]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])=[O:75])[C@H:53]([C:64]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:25]([NH:27][C@H:28]([C:41]([OH:43])=[O:42])[CH2:29][CH2:30][C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:26])[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:66])[C@@H:54]([CH3:63])[O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reaction time: 15 h

Procedure:
Boc-Ser(Bzl)-Ser(Bzl)-Glu(OBzl)-OH (71.6 g, 104 mmol) was treated with 2.7 liters of freshly prepared 3.9 N HCl in THF for 45 minutes. The mixture was evaporated to dryness and the residue evaporated twice more with THF to give a solid mass (59.3 g; mp 161°-165°). It was collected and washed with ether and stirred in 500 ml of DMF with Boc-Thr(Bzl)-OSu (38.2 g, 94 mmol) in the presence of Et3N (25 ml) at 0° for 1 hour and then at 25° for 15 hours. More Et3N (14.5 ml) was added in several portions during this time to maintain the reaction slightly basic. Some insoluble matter formed was filtered off and the filtrate evaporated to an oil which was dissolved in EtOAc (1.5 liters), washed with 5% HOAc, H2O (2 times), dried (Na2SO4), and evaporated to a solid mass. The product was recrystallized from EtOAc and petroleum ether to yield, 64.8 g (78.1%); mp 115°-118°; [α]D25 = +11.64° (c l, DMSO).
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]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1.CNC1C=CC=C(NC)N=1.C(N(CC)CC)C>ClCCl>[Si:19]([O:18][CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: C=CCCCCC(O)c1ccc2ccccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CNc1cccc(NC)n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of alcohol 181 (1.0 g, 4.16 mmol) in dichloromethane (40 mL) at room temperature under nitrogen atmosphere were successively added solid t-butyldimethylsilyl chloride (815 mg, 5.41 mmol), imidazole (340 mg, 4.99 mmol), and a catalytic amount of 2,6-dimethylaminopyridine. The mixture was stirred over 1 hour and triethylamine (696 μL, 4.99 mmol) was added. The mixture was stirred for 2 days. The reaction was quenched with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed successively with a 1N HCl (2×10 mL), a saturated solution of sodium bicarbonate and brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography using hexane as the eluent, and affording the title compound 182 in 84% yield (1.24 g). 1H NMR: (300 MHz, CDCl3) δ: 7.83-7.79 (m, 3H), 7.70 (s, 1H), 7.47-7.40 (m, 3H), 5.78 (ddt, J=17.0, 10.4, 6.6 Hz, 1H), 5.85-5.71 (m, 2H), 4.79 (dd, J=6.9, 4.9 Hz, 1H), 2.04-1.98 (m, 2H), 1.80-1.54 (m, 2H), 0.90 (s, 9H), 0.04 (s, 3H), −0.14 (s, 3H). MS (ESI)=223 (MH+-TBSO).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:16][CH3:17])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[O:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)[CH3:19].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][NH:16][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:18][CH3:19])[CH:25]=2)=[CH:3][CH:4]=1)[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CN[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CN[C@@H](CN1CCOCC1)c1ccc(-c2cccc(OC)c2)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
[(1R)-1-(4-Bromophenyl)-2-(4-morpholinyl)ethyl]methylamine (3.5 g, 11.7 mmol) was dissolved in a dioxane/H2O solution (140 mL, 5:2 volume ratio) at room temperature with magnetic stirring. The resulting solution was treated with 3-methoxylbenzene boronic acid (1.76 g, 12.9 mmol) followed by K2CO3 (4.85 g, 3.51 mmol) and PdCl2(dppf)2.CH2Cl2 (0.48 g, 0.59 mmol). The reaction was maintained at 100° C. for 5 h. The reaction mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated and then partitioned between EtOAc and brine. The organic layer was dried over MgSO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 80 mL/min, A: MeOH (with 10% NEt3), B: CH2Cl2, A: 2% for 20 min, 5% for 20 min, 10% for 10 min; detection at 254 nm) to give the title compound as a yellow oil (3.3 g, 85%). MS (ES) m/e 327 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:20]1[CH:23]=[C:24]([CH3:25])[C:17]([O:16][CH2:15][CH2:14][OH:13])=[C:18]([CH3:26])[CH:19]=1)=[N:1]2
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCO
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-4,6-difluoro-benzamide (0.96 g, 5.60 mmol), 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.09 g, 5.60 mmol), NaHSO3 (58.5 wt %, 1.00 g, 5.60 mmol) and p-toluenesulfonic acid monohydrate (1.44 g, 7.06 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 120° C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (100 mL). The solid separated was filtered and washed with water and dried under vacuum to give 5,7-difluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one as a white solid. Yield: 1.55 g (79%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1>Cl.O1CCOCC1.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([OH:17])=[O:16])[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CSc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(N(CC(=O)O)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Tert-butyl 2-(N-(4-(methylthio)phenyl)methylsulfonamido)acetate (220 mg, 0.664 mmol) was dissolved in HCl 4M in Dioxane (4 ml). The reaction was stirred at RT for 8 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under vacuum, and the crude product was triturated with Petroleum Ether to give 2-(N-(4-(methylthio)phenyl)methyl-sulfonamido)acetic acid (150 mg, 82% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[C:21]([CH3:30])[C:20]=1[CH3:31]>>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22](/[CH:23]=[CH:24]/[C:25]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[C:21]([CH3:30])[C:20]=1[CH3:31]
Reactant: COc1ccc(C=CC(=O)O)c(C)c1C
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3C)nc2n(CCC)c1=O
Yield: 48.3 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.31 g (10.24 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.42 g (15.4 mmol) of 4-methoxy-2,3-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.96 g (yield 48%) of Compound 12 as a white powder.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][NH:7][C:6]2=[N:10][CH:11]=[CH:12][C:5]=12.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ncnc21
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
To a 250 mL oven dried three-neck round bottom flask equipped with a stir bar, condenser, septa, nitrogen inlet and thermocouple was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 26 mL, 0.320 mol). The mixture was chilled to 0-5° C. To a oven dried 100 mL round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (42 mL, 0.520 mol), and the resulting slurry was then added portion wise via large bore canula over 15 minutes to the sodium hydride (NaH) suspension in THF. The reaction temperature rose to 6.8° C. after the addition of the substrate. The reaction mixture was stirred at 0-5° C. for 40 minutes before being charged neat triisopropylsilyl chloride (6.6 g, 7.24 mL, 0.0342 mol, 1.05 equiv) via syringe over 5 minutes. The cooling bath was removed and the reaction mixture was warmed to reflux for 4 hours. The reaction was monitored by TLC (80% hexane/ethyl acetate). When the reaction was deemed complete, the reaction mixture was cooled to room temperature and dilute with ethyl acetate (100 mL) and 20% aqueous brine (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic fractions were washed with 1M sodium bicarbonate (NaHCO3) aqueous solution (100 mL) and 20% aqueous brine (100 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10% ethyl acetate/hexane gradient elution) to afford 4-chloro-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine (3d, 10.0 g, 10.10 g theoretical, 99%) as an amber oil. For 3d: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.61 (s, 1H), 7.67 (d, 1H, J=3.7 Hz), 6.76 (d, 1H, J=3.5 Hz), 1.86 (m, 3H), 1.02 (d, 18H, J=7.5 Hz); C15H24ClN3Si (MW, 309.91), LCMS (EI) m/e 310/312 (M++H).