Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[NH:21][CH:20]([CH3:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:11][CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]([O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[CH:42]1[C:43]2[CH:31]([CH2:30][O:29][C:27]([N:21]3[C:16]4[CH:15]=[CH:14][C:13]([C:12]5[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]=[CH:10][CH:11]=5)=[CH:25][C:17]=4[C:18]([CH3:24])([CH3:23])[O:19][CH:20]3[CH3:22])=[O:28])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]=2[CH:39]=[CH:40][CH:41]=1
Reactant: CC1Nc2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2C(C)(C)O1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1OC(C)(C)c2cc(-c3cccn3C(=O)OC(C)(C)C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl-5-(2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate (1.7 g, 4.96 mmol), 9-fluorenylmethyl chloroformate (1.92 g, 7.5 mL), sodium carbonate (4 g, 37 mmol) in dioxane (50 mL) and water (50 mL) was stirred at room temperature under a blanket of nitrogen for 6 hours. Ethyl acetate (100 mL) was added and organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/6:1) to afford 9H-fluoren-9-ylmethyl-6-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1 (4H)-carboxylate as a clean oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11].ClCC1C=CON=1>>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([CH2:2][P:13]([O:14][CH2:15][CH3:16])(=[O:17])[O:12][CH2:10][CH3:11])[O:7][N:6]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(CCl)on1
Agent: ClCc1ccon1
Product: CCOP(=O)(Cc1cc(OC)no1)OCC
Yield: 56.1 %

Procedure:
3.8 g 5-chloromethyl-3-methoxy-isoxazole and 6.0 g of triethylphosphite were stirred at 150° C. until complete conversion of the chloromethyl isoxazole (2-8 h). Kugelrohr destillation gave 3.6 g of diethyl (3-methoxy-isoxazol-5-yl)-methane phosphonate. Bp. 160°-165° C./0.3 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.CC(C)=O>[CH:12]1([C:10]([NH:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([O:1][S:34]([C:32]4[S:33][C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=5)=[CH:30][CH:31]=4)(=[O:35])=[O:36])[CH:16]=[CH:15][C:5]=3[N:6]=2)=[O:11])[CH2:13][CH2:14]1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2s1)C1CC1
Yield: 8.5 %

Procedure:
A solution of cyclopropanecarboxylic acid (6-hydroxybenzothiazol-2-yl)amide (intermediate 6) (60 mg, 0.256 mmol), pyridine (80 μl, 0.991 mmol), 4-dimethylaminopyridine (3 mg, 0.025 mmol) and 5-(2-pyridyl)thiophene-2-sulfonyl chloride (99 mg, 0.384 mmol) in 2 ml of acetone is stirred for 24 hours at 40° C. The reaction medium is concentrated to dryness, taken up in 2 ml of DMSO and purified 4 times by preparative LC/MS (method B) to give 10 mg of 5-pyridin-2-ylthiophene-2-sulfonic acid 2-(cyclopropanecarbonyl-amino)benzothiazol-6-yl ester.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([C:21](=[O:55])[NH:22][C@H:23]([CH2:44][O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[C:24]([N:26]3[CH2:43][CH2:42][CH2:41][C:28]4([C:32](=[O:33])[N:31]([CH3:34])[CH2:30][CH:29]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:27]3)=[O:25])([CH3:20])[CH3:19])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:17][C:18]([CH3:20])([CH3:19])[C:21]([NH:22][C@H:23]([CH2:44][O:45][CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=1)[C:24]([N:26]1[CH2:43][CH2:42][CH2:41][C:28]2([C:32](=[O:33])[N:31]([CH3:34])[CH2:30][CH:29]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27]1)=[O:25])=[O:55]
Reactant: COc1ccc(COC[C@@H](NC(=O)C(C)(C)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1ccc(COC[C@@H](NC(=O)C(C)(C)N)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {1-[(R)-1-(4-Methoxy-benzyloxymethyl)-2-(2-methyl-1-oxo-4-phenyl-2,7-diaza-spiro[4.5]dec-7-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (70 mg, 0.09 mmol) in DCM (2 ml) was treated with piperidine (0.20 ml, 2.0 mmol). The resulting solution was stirred for 2 h at RT. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1.[CH2:23](O)[CH2:24]C>>[CH3:1][O:2][CH:3]([C:4]([O:6][CH2:7][CH2:23][CH3:24])=[O:5])[C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9]
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCO
Product: CCCOC(=O)C(OC)C(=O)OCCC

Procedure:
Dimethyl methoxymalonate (25.0 grams, 0.15 mole) and a large excess of n-propyl alcohol (250 millilaters) were reacted in the presence of p-toluenesulfonic acid (1.36 grams) catalyst, In a manner similar to that described in Example LIII Part A, to give 33.23 grams (0.15 mole) of di-n-propyl methoxymalonate. NMR analysis of the product indicated the following:
Reaction SMILES: CN(C[C:5]1[C:9]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:19])=[O:18].Cl[C:27]1C=CC=CC=1>>[N+:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]2[C:9]=1[CH:5]=[C:6]([CH2:27][CH:20]([N+:17]([O-:19])=[O:18])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:7]2)([O-:16])=[O:15]
Reactant: Clc1ccccc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2cccc([N+](=O)[O-])c12
Product: CCOC(=O)C(Cc1cc2c([N+](=O)[O-])cccc2[nH]1)[N+](=O)[O-]

Procedure:
A solution of 60 g of 4-nitrogramine [J. B. Hester, J. Org. Chem., 29, 1158 (1964)] and 54 g of ethyl nitroacetate in 1.2 L of chlorobenzene was heated at 100° C. for 1.5 h. After cooling the mixture was filtered, washed with cold methylene chloride and dried in vacuo to afford 58.9 g of ethyl 3-(4-nitro-2-indolyl)-2-nitropropionate as a yellow solid: mp 159°-160.5° C. Another 11 g may be recovered from the filtrate by dilution with hexane, preparative liquid chromatography [silica; methylene chloride/ethyl acetate (90:10)] and recrystalization from methanol. The structure was confirmed by NMR.
Reaction SMILES: ClC1C=C(Cl)C=CC=1[C:4](Cl)=[O:5].Cl[C:13]1[CH:28]=[CH:27][C:16]([C:17]([NH:19][C:20]2[CH:21]=[N:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[O:18])=[CH:15][CH:14]=1>>[OH:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:27]=[CH:28][C:13]([O:5][CH3:4])=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: COc1ccc(C(=O)Nc2ccc(O)nc2)cc1

Procedure:
Starting from 2,4-dichlorobenzoyl chloride (2.10 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][N:10]2[CH2:15][C:14]3[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:18]=[N:19][C:13]=3[NH:12][C:11]2=[O:25])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:45][NH:46][CH2:47][C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]([CH3:58])=[CH:50][CH:49]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH3:45][N:46]([CH2:47][C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]([CH3:58])=[CH:50][CH:49]=1)[C:22](=[O:23])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[N:19][C:13]2[NH:12][C:11](=[O:25])[N:10]([CH2:9][CH2:8][N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[CH2:15][C:14]=2[CH:16]=1
Reactant: CNCc1ccc(C)c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)c2ccccc12
Yield: 50 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(4-methyl-naphthalen-1-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (175 mg, 50%) was prepared as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.50 (br s, 1H), 10.14-10.09 (m, 1H), 8.41-8.30 (m, 1H), 8.16-7.85 (m, 3H), 7.69-7.53 (m, 3H), 7.40-7.01 (m, 3H), 5.37-4.85 (m, 4H), 4.65-4.46 (m, 2H), 3.99-3.93 (m, 2H), 3.78-3.31 (m, 6H), 3.20-2.98 (m, 5H), 2.65-2.63 (m, 3H); MS (ESI) m/e 500 (M+H)+.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@@H:6]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][N:4]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])#[N:2].N[CH2:27][CH2:28][SH:29]>O1CCCC1>[CH3:12][S:9]([O:8][C@H:6]1[CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[C@H:3]([C:1]2[S:29][CH2:28][CH2:27][N:2]=2)[CH2:7]1)(=[O:11])=[O:10]
Reactant: NCCS
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C#N)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C2=NCCS2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
To a solution of (2S,4R)-2-cyano-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2 g) in tetrahydrofuran (40 ml) was added 2-aminoethanethiol (630 mg) at ambient temperature. After stirring for 24 hours at the same temperature, the mixture was evaporated. The residue was extracted with dichloromethane, washed with water and brine successively, and dried over magnesium sulfate. The organic layer was evaporated, and then the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (4:l,V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-thiazolin-2-yl)pyrrolidine (0.96 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(Br)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-bromobenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 372 (M{81Br}+H+, 95), 370 (M{79Br}+H+, 100).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO[CH:35]1[CH:39]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH2:38][CH:37](OC)O1.N1C=CC=CC=1.Cl[Si](C)(C)C>ClCCCl>[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([N:31]1[CH:37]=[CH:38][C:39]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[CH:35]1)[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:20])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Reactant: COC1CC(c2ccncc2)C(OC)O1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccncc2)c1)C(C)(C)C
Reaction time: 72 h
Yield: 42.9 %

Procedure:
A solution of crude 3(R)-amino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl ester trifluoroacetate salt (0.44 mmol), 4-(2,5-dimethoxy-tetrahydro-furan-3-yl)pyridine (101 mg, 0.482 mmol), pyridine (156 μL, 1.92 mmol), and chlorotrimethylsilane (366 μL, 2.88 mmol) in 1,2-dichloroethane (5 mL) was heated at 90° C. After 3 days, the mixture was allowed to cool and concentrated in vacuo to give a brown oil which was purified via flash column chromatography with 0.5% HOAc/10% MeOH/CH2Cl2 as eluant to afford 90 mg (43%) of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-pyridin-4-yl-1H-pyrrol-1-yl)succinamic acid benzyl ester as a pale yellow powder, mp 130-3° C. 1H NMR (CD3OD): ∂ 8.36 (bs, 2H), 7.98 (d, 2H, J=4.4 Hz), 7.51 (d, 2H, J=5.0 Hz), 7.48 (t, 1H, J=1.8 Hz), 6.93 (t, 1H, J=2.5 Hz), 6.61 (dd, 1H, J=1.7,3.0Hz), 5.34 (t, 1H, J=7.6 Hz), 5.10 (dd, 2H, J=2.5, 14.3 Hz), 4.16 (s, 1H), 3.14 (dd, 1H, J=7.8 Hz, 16.5 Hz), 2.60 (d, 3H, J=3.4 Hz), 0.92 (s, 9H). IR (KBr): 3314, 2965, 1734, 1648, 1604, 1543, 1400, 1167 cm−1. HRFABMS: Calcd for C27H32N4O4Cs (M+Cs+): 609.1478. Found: 609.1499. Anal: Calculated for C27H32N4O4•0.1 CH2Cl2•MeOH: C, 65.27; H, 7.06; N, 10.83. Found: C, 65.52; H, 6.89; N, 10.52.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]1([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[C:12]1([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:28]3[CH:27]=[C:26]4[C:31]([CH:32]=[CH:33][C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:25]4)=[CH:30][CH:29]=3)=[CH:3]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2-c1ccccc1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2-c1ccccc1

Procedure:
Following the general procedure for the Suzuki coupling, 5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (27 mg, 0.080 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (26.5 mg, 0.080 mmol), Na2CO3 (22 mg, 0.21 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) in DMF (2.5 mL)/water (0.5 mL). The crude material was purified by chromatography on an SCX column (1 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2 (13-33)→2% MeOH in CH2Cl2 (34-40)], yielding the title compound as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ=5.31 (brs, 2H), 7.38-7.42 (m, 1H), 7.43 (s, 1H), 7.47-7.52 (m, 1H), 7.53-7.59 (m, 4H), 7.75 (dd, J=2.0, 8.4 Hz, 1H), 7.75-7.79 (m, 2H), 7.94 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 8.18-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.35-8.37 (m, 1H), 8.44 (s, 1H). MS (ES+): m/z 414.0 (25) [MH+]. HPLC: tR=3.4 min (OpenLynx, polar—5 min).
Reaction SMILES: [Br:1]CC1C=CC(S(C)(=O)=O)=C(F)C=1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[Na+].[CH3:24][CH:25]([S:27]([O-:29])=[O:28])[CH3:26]>>[Br:1][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1F
Reactant: CC(C)S(=O)[O-]
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Product: CC(C)S(=O)(=O)c1ccc(CBr)cc1

Procedure:
The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluorobenzaldehyde and by replacing methane sulfinic acid sodium salt with 2-propanesulfinic acid sodium salt.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH3:32])[C:16]=2[CH:33]=1.[C:40](Cl)(=[O:42])[CH3:41].O>C1COCC1>[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:37])[CH3:38])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH2:32][C:40](=[O:42])[CH3:41])[C:16]=2[CH:33]=1
Reactant: Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
LiHMDS (11.5 mL, 1.0 M in THF) was added under nitrogen atmosphere at −78° C. to a suspension of dimethylcarbamic acid 6-chloro-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-3) (4.0 g, 9.60 mmol) in anhydrous THF (100 mL), and the mixture was stirred at −78° C. for 30 minutes and at 0° C. for 30 minutes. Acetyl chloride (1.36 mL, 19.2 mmol) was then added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was obtained by vacuum concentration, and purified by column chromatography (ethyl acetate:hexane=1:3) to yield the title compound (1.28 g, 29%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[F:13][B-](F)(F)F.F[B-](F)(F)F.F[N+]12CC[N+](O)(CC1)CC2.C(#N)C.NC1C=CC=CC=1>C(OCC)(=O)C>[Cl:9][C:8]1[C:7]([F:13])=[C:5]([C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]=1[Cl:1])[NH2:6]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: F[B-](F)(F)F
Agent: O[N+]12CC[N+](F)(CC1)CC2
Solvent: CC#N
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1F
Temperature: 25 °C
Yield: 36.6 %

Procedure:
4,5-Dichloro-2-nitroaniline (9.8 g, 47.4 mmol), 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (18.5 g, 57.4 mmol, Allied Signal, Buffalo), and acetonitrile (300 mL) were combined and the mixture was heated to reflux for several hours. After thin-layer chromatography showed that no starting aniline remained, the mixture was allowed to cool to rt and was poured into ethyl acetate, causing a precipitate to form. The mixture was filtered through a pad of Celite, purified by silica gel and the solvents were removed in vacuo to provide a brown solid (3.9 g, 37%); 1H NMR (DMSO-d6) δ: 8.11 (d, J=2.2 Hz, 1H, Ar—H), 7.67 (br s, 2H, NH2).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@H:49]([NH:51][C:12]([C@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: C[C@@H](N)c1nc2ccc(F)cc2s1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CC(C)OC(=O)N[C@@H](C(=O)N[C@H](C)c1nc2ccc(F)cc2s1)C(C)C
Yield: 60.8 %

Procedure:
In 500 ml of toluene, 10.2 g (0.05 mol) of N-isopropoxycarbonyl-D-valine was dissolved. Thereto were dropwise added, at −5° C., 12.4 g (0.0125 mol) of N-methylmorpholine and 6.8 g (0.05 mol) of isobutyl chlorocarbonate. Thereto was added, at −5° C., 18.3 g (0.05 mol) of (R)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate. A reaction and a post-treatment were conducted in the same manner as in Reference Example 1, and the suspension of a solid in toluene was filtered to collect the solid. The solid was subjected to Soxhlet extraction for 1 week, and the extract was concentrated to obtain a solid. The solid was recrystallized from xylene to obtain 11.6 g (yield: 62.7%) of isopropyl {(R)-1-[(R)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](Br)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:33][O:34][C:35](=[O:72])[NH:36][CH:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:62]=[CH:61][C:60]3[C:55](=[CH:56][CH:57]=[C:58](B4OC(C)(C)C(C)(C)O4)[CH:59]=3)[CH:54]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([C:58]2[CH:57]=[CH:56][C:55]4[C:60](=[CH:61][CH:62]=[C:53]([C:50]5[NH:49][C:48]([CH:44]6[CH2:45][CH2:46][CH2:47][N:43]6[C:41](=[O:42])[CH:37]([NH:36][C:35]([O:34][CH3:33])=[O:72])[CH:38]([CH3:40])[CH3:39])=[N:52][CH:51]=5)[CH:54]=4)[CH:59]=2)[CH:25]=[CH:24]3)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)ccc3c2)[nH]1)C(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
(1-{2-[5-(6-Bromonaphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.174 g), [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.202 g), and NaHCO3 (0.108 g) were dissolved in a mixture of 1,2-dimethoxyethane (6 mL) and water (2 mL). The solution was degassed with nitrogen, and Pd(PPh3)4 (0.0176 g) was added. The reaction mixture was stirred at 85° C. for 16 hours and evaporated under vacuum. Solid was dissolved in ethyl acetate (10 mL) and extracted twice with water (10 mL) and once with brine (10 mL) Solution was evaporated, dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving (1-{2-[5-(6′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[2,2]binaphthalenyl-6-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.050 g, 16%) as a white solid: 1H-NMR: 300 MHz, (MeOH-d4) δ: 8.3 (m, 4H), 8.1 (m, 6H), 8.0 (s, 2H), 7.8 (d, J=9.4, 21-1), 5.3 (m, 2H), 4.3 (d, J=9.0, 2H), 4.1 (m, 2H), 3.9 (m, 2H), 3.7 (s, 6H), 2.6 (m, 2H), 2.2 (m, 6H), 0.9 (m, 12H); MS (ESI) m/z 839 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([N:7](C=O)[NH2:8])=[NH:6])[CH3:2].[CH3:12]OCCOCCOC>>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[CH:12][NH:8][N:7]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C(=N)N(N)C=O
Reactant: COCCOCCOC
Product: CCOC(=O)c1nc[nH]n1
Yield: 85 %

Procedure:
A suspension of (N-Formylhydrazino)-imino acetic acid ethyl ester (9.62 g, 60.4 mmol) in diglyme (40 ml) was refluxed for 30 minutes. After cooling, the precipitated crystal was collected by filteration and washed with hexane to give 1H-1,2,4-triazol-3-carboxylic acid ethyl ester (7.28 g) Yield: 85%.