Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>C1COCC1>[CH3:5][Si:4]([CH2:3][C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: O=C1CCCCC1
Reactant: C[Si](C)(C)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CC1(O)CCCCC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A flask was charged with 27.9 g of magnesium and 250 ml of THF, to which a solution of 135 g of chloromethyltrimethylsilane diluted with 150 ml of THF was added dropwise at 50° C. The addition was followed by one hour of stirring at 65° C., after which 98.1 g of cyclohexanone was added dropwise below 20° C. After one hour of stirring at room temperature, an aqueous solution of ammonium chloride was added for hydrolysis. This was followed by ordinary post-treatments. Upon vacuum distillation, there was obtained 141.6 g (yield 76%) of 1-trimethylsilylmethylcyclohexanol.
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[N:15][CH:16]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([O:46]C(=O)C)[CH:38]=2)[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([NH:10][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([CH2:36][C:30]3[C:31](=[O:35])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[C:28](=[O:51])[C:29]=3[CH3:50])=[CH:38][C:39]=2[OH:46])=[CH:12][CH:13]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(Cl)nc3)c(O)c2)=C(C)C1=O
Yield: 17.5 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (61 mg, 0.361 mmol), 5-amino-2-chloropyridine (46 mg, 0.361 mmol) and triethylamine (36 mg, 0.361 mmol) were added to a methylene chloride solution (3 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (45 mg, 0.120 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (10 mg, 0.021 mmol, 17%).
Reaction SMILES: I[C:2]1[C:6]2=[N:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:31][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>CC(O)C.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:2]2[C:6]3=[N:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:10]=[C:5]3[N:4]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:3]=2)[CH:30]=[N:31][CH:32]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1ccc2c(n1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(n1)c(-c1cncc(OC)c1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 59.1 %

Procedure:
A glass microwave reaction vessel was charged with methyl 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.300 g, 0.658 mmol), 5-methoxy-3-pyridineboronic acid pinacol ester (0.216 g, 0.921 mmol, Sigma-Aldrich), and K3PO4 (0.419 g, 1.973 mmol) in 70% i-PrOH in H2O (3.30 mL). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 10 min. 2 M HCl (aq.) was added and the mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (eluting with 0-10% MeOH in DCM) to provide methyl 3-(5-methoxy-3-pyridinyl)-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate (0.170 g, 0.389 mmol, 59.1%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 438.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 2.37 (3H, s), 3.96 (3H, s), 4.00 (3H, s), 7.29 (2H, d, J=8.22 Hz), 7.79-7.85 (2H, m), 8.16-8.21 (2H, m), 8.27-8.34 (2H, m), 8.42 (1H, d, J=8.61 Hz), 8.81 (1H, d, J=1.56 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:29][C:28]([CH3:31])([CH3:30])[CH:27]=[CH:26][C:6]2=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[CH:13]=[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=[C:10]([N+:22]([O-])=O)[C:9]=1[N:8]2[CH3:25].O>C(O)(=O)C.[Zn]>[NH2:22][C:10]1[C:9]2[N:8]([CH3:25])[C:7]3[C:16](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]4[O:29][C:28]([CH3:30])([CH3:31])[CH:27]=[CH:26][C:6]4=3)[C:15](=[O:17])[C:14]=2[CH:13]=[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=12
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4c([N+](=O)[O-])c1n3C)C=CC(C)(C)O2
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4c(N)c1n3C)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 178 mg of the compound obtained in Step 6 above in 10 ml of acetic acid and 1 ml of water there are added 621 mg of zinc wool. The reaction mixture is stirred at ambient temperature for 2.5 hours and is then filtered. The filtrate is made alkaline using 10% aqueous ammonium hydroxide solution; the precipitate formed is then separated off by filtration. The crude residue is purified by chromatography over silica gel (dichloromethane/methanol: gradient from 0.1 to 0.5%), allowing the expected product to be isolated.
Reaction SMILES: [Li+].[OH-].Br[C:4]1[C:12]2[S:11][CH:10]=[C:9]([CH:13]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[C@@H:14]([C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:15][CH2:16][CH2:17][CH3:18])[C:8]=2[CH:7]=[C:6]([F:42])[CH:5]=1.[CH3:43][N:44]1[C:48](B2OC(C)(C)C(C)(C)O2)=[CH:47][CH:46]=[N:45]1>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].O1CCOCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:13]([C:9]2[C:8]3[CH:7]=[C:6]([F:42])[CH:5]=[C:4]([C:48]4[N:44]([CH3:43])[N:45]=[CH:46][CH:47]=4)[C:12]=3[S:11][CH:10]=2)[C@@H:14]([C:19]2[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:36][CH:37]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(F)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1csc2c(-c3ccnn3C)cc(F)cc12

Procedure:
Dioxane (1.4 mL) and LiOH (2.0 M in water, 0.68 mL, 1.36 mmol) were added to a mixture of ethyl N-(4-{(1S)-1-[(7-bromo-5-fluoro-1-benzothien-3-yl)(4-chlorophenyl)methyl]pentyl}benzoyl)-β-alaninate (23.0 mg, 0.036 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (11.0 mg, 0.053 mmol), and PdCl2(dppf) (0.029 g, 0.036 mmol) in a sealed microwave vial under a nitrogen atmosphere. The mixture was degassed then irradiated in a microwave reactor at 80° C. for 15 minutes. The mixture was acidified with acetic acid then extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by preparative reverse-phase HPLC eluting with acetonitrile/water+0.1% TFA. The resulting material was further purified by silica gel chromatography eluting with 5% MeOH/DCM+0.5% acetic acid to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 7.57 (br, 3H); 7.29-7.37 (m, 6H); 7.23 (d, J=6 Hz, 2H); 6.94 (d, J=7 Hz, 1H); 6.86 (br, 1H); 6.40 (br, 1H); 4.47 (d, J=11 Hz, 1H); 3.71 (br, 3H); 3.62 (br, 2H); 3.43 (t, J=9.5 Hz, 1H); 2.59 (br, 2H); 1.45-1.52 (m, 2H); 1.13-1.16 (m, 1H); 1.04-1.06 (m, 1H); 0.88-1.00 (m, 2H); 0.68 (t, J=6.5 Hz, 3H). LC1: 3.99 min. (M+H)+ 618.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.CI.[H-].[Na+].[C:17](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CS(C)=O>[Cl:1][C:2]1[N:3]([CH3:17])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cn1c(Cl)c(C=O)c2ccccc21

Procedure:
2-Chloroindole-3-carboxaldehyde (2.69 g) and methyl iodide (4.26 g) were dissolved in a mixed solvent of tetrahydrofuran (25 ml) and dimethylsulfoxide (25 ml), and sodium hydride (0.66 g, 60% mineral oil dispersion) was added thereto at 0° C. A 10% aqueous solution of citric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then a saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was washed with hexane (30 ml) to give 2-chloro-1-methylindole-3-carboxaldehyde (2.54 g).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH:12]([OH:39])[CH:13]([S:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:15]=3)=[CH:8][C:6]=2[N:7]=1)#[N:2].O1C2C=CC=CC=2N=C1>>[C:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH:12]([OH:39])[CH:13]([S:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:15]=3)=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: COC(=O)CCSC(c1cccc(OCc2ccc3ccccc3n2)c1)C(O)c1ccc2oc(C#N)nc2c1
Agent: c1ccc2ocnc2c1
Product: N#Cc1nc2cc(C(O)C(SCCC(=O)O)c3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1

Procedure:
When the 1-hydroxy ester obtained in Example 64, Step 2, above, is substituted for the ester in Example 31, 1-cyano-5-(1-hydroxy-2-((2-carboxyethyl)thio) -2-(3-quinolin-2-yl-methyloxy)phenyl)ethyl)benzoxazole is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.ClCCl>O1CCOCC1.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]>[CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([C:33]1[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)c1c(n2Cc2ccccc2)CCCC1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 9-benzyl-6-bromo-2,3,4,9-tetrahydro-1H-carbazole (2.217 g, 6.516 mmol) was reacted with aqueous 2M K2CO3 (6.5 ml), 4-methoxyphenylboronic acid (1.188 g, 7.819 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.106 g, 0.130 mmol) in dioxane (65 ml) to give the product (1.94 g, 5.28 mmol, 81%) as a viscous brown oil. 1H NMR (DMSO-d6) δ 1.79-1.86 (m, 4H), 2.63-2.71 (m, 4H), 3.78 (s, 3H), 5.33 (s, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.03 (d, J=7.5 Hz, 2H), 7.21 (t, J=7.0 Hz, 1H), 7.25-7.30 (m, 3H), 7.38 (d, J=8.6 Hz, 1H), 7.56-7.58 (m, 3H); [ESI(+)], m/z 368 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]2[N:16]([C:17]([O:19][C@@H:20]3C4CCN(CC4)[CH2:21]3)=[O:18])[CH2:15][CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)=[CH:5][CH:6]=1.C1([C@H]2C3C(=CC=CC=3)CCN2)C=CC=CC=1.ClC(OCC)=O>>[C:4]1([C@H:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14][CH2:15][N:16]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Agent: CCOC(=O)Cl
Agent: c1ccc([C@@H]2NCCc3ccccc32)cc1
Product: CCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1

Procedure:
According to the process disclosed in U.S. Pat. No. 6,017,927, Solifenacin may be prepared by condensation of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of formula (III) with ethyl chloroformate to produce (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate of formula (IV), which is further reacted with (R)-(−)-3-quinuclidinol of formula (V) to produce Solifenacin (II). Solifenacin is converted to Solifenacin hydrochloride by treating with HCl.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:21][CH:22]([C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24])[C:26]([NH:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)=[O:27]
Reactant: Cc1ccc(CNC(=O)C(C)C(=O)O)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: Cc1ccc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1

Procedure:
The title compound, MS: m/e=468.2 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(4-methyl-benzyl)-malonamic acid.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1ccccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccccc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (5 g), 2-bromo-1-(2-methoxyphenyl)ethanone (3.3 g) and N,N-dimethylformamide (200 mL) was added 60% sodium hydride (1 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (4.12 g, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2ccccc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
In a 100 ml flask, 3-nitro-quinolin-4-ol (500 mg, 2.629 mmol) was dissolved in methanol (50 ml) and 10% palladium on active carbon (1.2 g, 10 w/w %) was added thereto and then stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered on celite and then evaporated under reduced pressure to obtain brown liquid (445 mg, quantitative yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([CH3:24])[N:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:16][C:17]1[N:18]=[C:19]([CH3:24])[N:20]=[C:21]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:15])[CH:22]=1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc(Cl)cc(N2CCN(c3cnccc3C3CC3)C2=O)n1
Yield: 15.4 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 4,6-dichloro-2-methylpyrimidine (80.2 mg, 0.492 mmol), 1,4-dioxane (5 mL), copper iodide (9.3 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (6.9 mg, 0.049 mmol) and potassium phosphate (313 mg, 1.47 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 25 mg of the product (15% yield).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:18][S:19]C(=O)C)[C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([CH2:18][SH:19])[C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: N
Product: O=C1C[C@@H](C(=O)O)N(C(=O)C(CS)CS)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield (S)-1-(3-mercapto-2-mercaptomethyl-1-oxopropyl)-4-oxo-L-proline.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>ClCCl.CCCCCC>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([O:1][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Oc1cccc2sccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc2sccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Into a solution of 4-hydroxybenzo[b]thiophene (7.60 g, 50.6 mmol) and tert-butyldimethylsilyl chloride (8.39 g, 55.7 mmol) in dichloromethane (300 mL) is added imidazole (3.79 g, 55.7 mmol) and the mixture is stirred overnight at ambient temperature. The mixture is diluted with hexane (500 mL), filtered and concentrated to a pink oil. The crude material is subjected to chromatography on silica (in hexane) to provide the title compound as a colorless oil (12.9 g, 96% yield).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[F:31])C=CC=CC=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.C(OCC)(=O)C.O>CS(C)=O.CO>[CH:33]1([NH:36][C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[F:31])=[O:7])[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)c2cc1OC
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1OC
Yield: 73.2 %

Procedure:
4-(6,7-Dimethoxyquinolin-4-yloxy)-2-fluorophenylcarbamic acid phenyl ester (109 mg, 0.250 mmol) and cyclopropylamine (28.5 mg, 0.500 mmol) were stirred in dimethylsulfoxide (1 ml) at room temperature for 2 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=50:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (73 mg, 0.183 mmol, 73%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[O:20])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:5]2=[CH:4][CH:3]=1.[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[Cl:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:20]
Reactant: O=C(OCc1cccc(Cl)c1)c1cc2nc(Cl)ccc2n1Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3cccc(Cl)c3)n2Cc2cccc(Cl)c2)n1
Temperature: 140 °C

Procedure:
3-Chlorobenzyl 5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (0.210 g, 0.471 mmol, from Step 2), di-tert-butyl hydrazine-1,2-dicarboxylate (0.12 g, 0.52 mmol, Aldrich) and Cs2CO3 (0.15 g, 0.47 mmol, Aldrich) were combined in toluene (4.2 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.037 g, 0.047 mmol, Aldrich) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction mixture was heated to 140° C. for 30 minutes. Upon cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted three times and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Flash chromatography (eluting with a slow gradient from 0-20% EtOAc in hexanes, hold, then increase rapidly up to 80% EtOAc in hexanes) afforded purified product (146 mg, 48%). LCMS (M+H)+: 641.0643.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[CH:5]=[CH:6][CH:7]=1.ClCCl.N1C=CC=CC=1.[C:27](Cl)(=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30]>C(OCC)(=O)C>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:27](=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH:3]=1)=[O:17]
Reactant: Nc1cccc(NC(=O)c2ccccc2Br)c1
Reactant: CC(C)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1cccc(NC(=O)c2ccccc2Br)c1

Procedure:
N-(3-Aminophenyl)-2-bromobenzamide (50 mg, 0.17 mmol), dichloromethane (1.7 mL), pyridine (17 μL, 0.21 mmol), and isovaleryl chloride (25 μL, 0.21 mmol) were added to a vial with stir bar and stirred for 20 h. The reaction was then diluted with ethyl acetate, then the combined organics were washed with 1 M aqueous HCl, then half-saturated aqueous NaHCO3, then brine. The crude solution was dried over Na2SO4, filtered, and concentrated to a colorless oil, then purified by column chromatography (EtOAc/hexanes gradient) after dry-loading on SiO2. The title compound was obtained as a white solid (53 mg, 82%). LRMS (ESI+) (M+H): 375.05.