Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:31]([O:33][CH3:34])=[O:32])=[C:26]2[C:30]=1[O:29][CH2:28][CH2:27]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)CC(O)C>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:31]([O:33][CH3:34])=[O:32])=[C:26]5[C:30]=4[O:29][CH2:28][CH2:27]5)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(N)c2c1CCO2
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CC(C)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)OC)c4c3OCC4)nc2N1C1CCCC1
Yield: 74.1 %

Procedure:
(7R)-2-Chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (670 mg, 2.30 mmol), methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate 1g (440 mg, 2.30 mmol) and p-toluenesulfonic acid (700 mg, 3.68 mmol) were dissolved in 25 mL 4-methyl-2-pentanol. The resulting solution was heated to reflux for 6 hours with stirring. The reaction solution was added with 25 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (50 mL×3) and saturated sodium chloride solution (50 mL×3) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylate 1p (0.77 g, yield: 74.0%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:31])=[CH:33][CH:34]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(=O)c5ccccc5)cc4)cc23)CC1
Yield: 74.8 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 30.0 mg (0.131 mMol) 4-(benzoyl)benzoic acid, 14.4 mg (75%) of the title compound were recovered.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[C:28](Cl)[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:28]2[C:29]([Cl:33])=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[N:27]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(F)c1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(Cl)c(Cl)cc3Cl)CC2)c(F)c1
Yield: 72.7 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-3-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (405 mg) described in Preparation Example 158 and 2,3,5,6-tetrachloropyridine (390 mg), the title compound (452 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Br:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Agent: Cl
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 116–118° C.; 1H NMR (300 MHz, CDCl3): δ 6.98 (s, 1 H), 6.67 (s, 1 H), 6.58 (d, J=2.2 Hz, 1 H), 4.97–4.95 (m, 1 H), 4.38 (t, J=7.9 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.6, 5.9 Hz, 1 H), 3.56 (dd, J=10.6, 3.6 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.9 Hz, 2 H), 2.06 (s, 3 H), 1.92–1.72 (m, 2 H), 0.94 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C19H25N3O3Br (M+H)+: 422.1079; found m/z 422.1097.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=[C:11]2[CH:10]([OH:26])[N:9]=1.[CH3:27]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=[C:11]2[CH:10]([O:26][CH3:27])[N:9]=1
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(O)N=C2c1ccccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(OC)N=C2c1ccccc1Cl

Procedure:
To a solution of 0.86 g. of 6-(2-chlorophenyl)-8-ethyl-4-hydroxy-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]-diazepine-2-carboxamide in 20 ml. of methanol is added one drop of concentrated sulfuric acid. The resulting mixture is refluxed for 5 minutes. After evaporation of the solvent a saturated sodium hydrogen carbonate solution is added to the residue, and the resulting precipitate is collected by filtration to give 6-(2-chlorophenyl)-8-ethyl-4-methoxy-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxamide as crystals melting at 200° to 201° C. This product is identical with the product obtained in Example 3 with respect to the melting point and infra red absorption spectrum thereof.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:19]=3[C:20]#[N:21])[CH2:13][CH2:12]2)[CH2:5][CH2:4]1.[C:27](O)(=[O:29])[CH3:28]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]([O:17][CH:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C@H:6]3[CH2:7][CH2:8][C@H:3]([NH:2][C:27](=[O:29])[CH3:28])[CH2:4][CH2:5]3)[CH2:16][CH2:15]2)=[C:19]([C:20]#[N:21])[CH:22]=1
Reactant: CC(=O)O
Reactant: N#Cc1cc(Cl)ccc1OC1CCN(CC[C@H]2CC[C@H](N)CC2)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(Cl)cc3C#N)CC2)CC1

Procedure:
The title compound was prepared analogously to example 59.5 from 2-{1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yloxy}-5-chloro-benzonitrile hydrochloride and acetic acid. MS (m/z): 404.5 (M+H+).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH3:31][NH:32][C:33]([C:35]1([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60])[CH2:43][C:42]2[C:37](=[C:38]([O:50]C)[C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[C:41]=2[O:44]C)[CH2:36]1)=[O:34]>O>[CH3:31][NH:32][C:33]([C:35]1([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][OH:60])[CH2:43][C:42]2[C:41](=[O:44])[C:40]([O:46][CH3:47])=[C:39]([O:48][CH3:49])[C:38](=[O:50])[C:37]=2[CH2:36]1)=[O:34]
Reactant: CNC(=O)C1(CCCCCCCCO)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)C1(CCCCCCCCO)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
A water (1.0 ml) solution of CAN (828 mg, 1.51 mmols) was dropwise added to an acetonitrile (5.0 ml) solution of N-methyl-2-(8-hydroxyoctyl)-4,5,6,7-tetramethoxy-2-indancarboxamide (255 mg, 0.602 mmols), with cooling with ice, and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:2) followed by recrystallization from ethyl acetate to obtain the entitled compound (106 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O:12][C:13](=O)[CH:14]([CH3:18])[C:15]([CH3:17])=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:3]=1[N:4]=[C:15]([CH3:17])[C:14]([CH3:18])=[C:13]2[OH:12]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Cc1ccc(N)c(Cl)c1
Product: Cc1cc(Cl)c2nc(C)c(C)c(O)c2c1

Procedure:
Prepared according to procedure R using 2-chloro-4-methyl-aniline (2.0 mL, 16.3 mmol), ethyl-2-methyl-acetoacetate (4.6 mL, 32.5 mmol), and PPA (8.12 g, 81.2 mmol) to afford 8-chloro-2,3,6-trimethylquinolin-4-ol.
Reaction SMILES: CN1CC[O:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[C:12]([C:14]1([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=2[CH3:30])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].C(Cl)(=O)C>>[C:4]([N:17]1[CH2:16][CH2:15][C:14]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=2[CH3:30])([C:12](=[O:13])[C:11]2[CH:10]=[C:9]([CH3:8])[CH:34]=[C:33]([CH3:35])[CH:32]=2)[CH2:19][CH2:18]1)(=[O:5])[CH3:3]
Reactant: COc1cccc(C(=O)NC2(C(=O)c3cc(C)cc(C)c3)CCNCC2)c1C
Reactant: CN1CCOCC1
Solvent: CC(=O)Cl
Product: COc1cccc(C(=O)NC2(C(=O)c3cc(C)cc(C)c3)CCN(C(C)=O)CC2)c1C
Reaction time: 48 h

Procedure:
A 25 mL vial was charged with a magnetic stir bar and morpholinomethylpolystyrene (PS-NMM, ˜300 mg, 1.92 mmol/g, 0.6 mmol). A solution of N-[4-(3,5-dimethyl-benzoyl)-piperidin-4-yl]-3-methoxy-2-methyl-benzamide (76 mg, 0.2 mmol in 2 mL CH2Cl2) was added, followed by acetyl chloride (16 μL, 0.22 mmol). The mixture was stirred for 2 days, filtered, and fractionated on a 2 g silica gel cartridge, eluting with a 0-100% ethyl acetate in hexanes gradient to provide N-[1-acetyl-4-(3,5-dimethyl-benzoyl)-piperidin-4-yl]-3-methoxy-2-methyl-benzamide. 1H NMR (500 MHz, CDCl3) δ(ppm): 7.6 (s, 2H), 7.15 (m, 2H), 6.87 (d, 2H), 6.7 (d, 1H), 4.17 (dt, 1H), 3.8 (s, 3H), 3.78 (m, 1H), 3.45 (t, 1H), 3.25 (t, 1H), 2.5 (m, 1H), 2.35 (m, 1H), 2.32 (s, 6H), 2.2 (m, 1H), 2.17 (m, 1H), 2.05 (s, 3H), 1.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[CH2:12]([N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]1SC)[CH3:13].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:15]1[N:14]([CH2:12][CH3:13])[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[N:16]=1
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: CCn1c(SC)nc(C(F)(F)F)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(Nc2cc(Cl)ccc2Cl)nc(C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
2,5-Dichloroaniline (0.49 g, 3.0 mmol) was dissolved in DMF (20 ml), and sodium hydride (60% oil, 0.20 g, 5.01 mmol) was added, followed by stirring at room temperature for 20 minutes. Then, 3-ethyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (1,14 g, 4.80 mmol) synthesized in the above was added, followed by stirring at 80° C. for 4 hours. After completion of the reaction, ice-water (30 ml) and ethyl acetate (30 ml) were added to the reaction solution to separate the organic layer, and then the aqueous layer was extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with saturated sodium bicarbonate aqueous solution (50 ml), water (50 ml×2) and saturated brine (80 ml) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. The thus obtained crude product was purified by a silica gel column chromatography (hexane: ethyl acetate=10:1) and then recrystallized from toluene, thereby obtaining yellow crystals of 2-(2,5-dichlorophenyl)amino-3-ethyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 6].
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][N:28]3[C:31](=[O:33])[CH3:32])=[CH:24][CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=C3C(CCN3C(=O)C)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:31]([N:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([N:15]([CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:13](=[O:14])[NH:12][C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:8][N:9]=3)[CH:30]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc3c(c2)N(C(C)=O)CC3)s1
Agent: CC(=O)N1CCc2ccc(NCC3CCCC3)cc21
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC(=O)N1CCc2ccc(N(CC3CCCC3)C(=O)Nc3ncc(SCC(=O)O)s3)cc21

Procedure:
The title compound was prepared via {2-[3-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]thiazol-4-yl}-acetic acid, using 1-[6-(cyclopentylmethyl-amino)-2,3-dihydro-indol-1-yl]-ethanone and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:4][CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=2)[C:26]([Sn](CCCC)(CCCC)CCCC)=[N:25]1.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.[Cu]I>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:34])([F:35])[F:36])[CH:31]=2)[C:26]([C:2]2[N:7]=[C:6]3[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]3=[N:4][CH:3]=2)=[N:25]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(F)(F)F)ccc12
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(C(F)(F)F)ccc34)nc12
Temperature: 90 °C
Yield: 50.4 %

Procedure:
A mixture of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (0.3 g, 0.81 mmol), 1-methyl-3-(tributylstannyl)-6-(trifluoromethyl)-1H-indazole (0.98 g, 1.51 mmol), Pd(PPh3)4 (174 mg, 0.151 mmol) and CuI (58 mg, 0.302 mmol) in dry DMF (10 mL) was heated to 90° C. for 3 hours. Water (10 mL) was added. The formed precipitate was separated by filtration, washed with petroleum ether (3 mL) to afford methyl 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (200 mg, 50%) as a white solid. LCMS: (M+H)+=490.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH3:16][NH2:17].O.Cl>CS(C)=O>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]2[C:2]=1[N:17]([CH3:16])[C:13](=[O:15])[CH2:12]2
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Reactant: CN
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Crude (2,3-difluoro-5-nitrophenyl)acetic acid (12, 1.00 g, 0.00461 mol) and a 40% solution of methylamine in water (3 eq., 1.20 ml, 0.0138 mol) are mixed in DMSO (5 ml) and stirred at 45° C. for 1 hour. 2N Hydrochloric acid (20 ml) is added in one portion and the mixture stirred at room temperature for 1 hour. The reaction mixture is extracted with ethyl acetate and the extract washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography (50% ethyl acetate/hexane) to give the title compound as a solid. HPLC r.t. 4.4 min.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@H:10]2[C@H:15]([C:16]([OH:18])=O)[CH2:14][CH2:13][O:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:59][C:60]1[CH:72]=[CH:71][C:63]([CH2:64][C@@H:65]2[CH2:70][CH2:69][CH2:68][NH:67][CH2:66]2)=[CH:62][CH:61]=1>ClCCl>[F:59][C:60]1[CH:61]=[CH:62][C:63]([CH2:64][C@@H:65]2[CH2:70][CH2:69][CH2:68][N:67]([C:16]([C@@H:15]3[CH2:14][CH2:13][O:12][CH2:11][C@H:10]3[NH:9][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[O:18])[CH2:66]2)=[CH:71][CH:72]=1
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Reactant: C[C@@H](N[C@@H]1COCC[C@H]1C(=O)O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](N[C@@H]1COCC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A cloudy solution of (3S,4R)-3-[(R)-1-Phenyl-ethylamino]-tetrahydro-pyran-4-carboxylic acid (containing sodium chloride; 943 mg, 2.57 mmol) in dichloromethane (25 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (1.61 g, 3.09 mmol) and triethylamine (826 μL, 5.92 mmol) and stirred for 5 minutes. A solution of the (S)-3-(4-fluorobenzyl)-piperidine prepared above in dichloromethane (5 mL) was added and the mixture was stirred at room temperature. After 18 h, the mixture was washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (75% ethyl acetate/hexanes) to provide the product as a gum (1.10 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Reactant: O=C=NCc1ccccc1
Product: CC1(C)CN(Cc2ccccn2)c2ccc(OC(=O)NCc3ccccc3)cc21

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (15.5 mg, 51%) having the following characteristics.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:12]1
Reactant: N#Cc1ccccc1F
Reactant: CN1CCCC(O)C1
Product: CN1CCCC(Oc2ccccc2C#N)C1

Procedure:
2-Fluoro-benzonitrile was reacted with 1-methyl-piperidin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 217 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C1([O:22][C:23]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:23]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: Brc1ccc(OCC2CCNCC2)cc1
Product: CCOC(=O)COC(=O)N1CCC(COc2ccc(Br)cc2)CC1

Procedure:
The procedure described in Example 4.3. is repeated. Starting from 1.6 g (5.9 mmol) of 4-{[(4-bromophenyl)oxy]methyl}piperidine, prepared in Step 5.2., and from 1.32 g (5.9 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}acetate, prepared in accordance with Example 1.1., gives the product in oil form.
Reaction SMILES: Cl.[S:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[CH2:32]([O:31][CH2:30][C@H:12]([NH:11][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][S:2][CH2:3]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCSC1
Agent: Cl
Product: O=C(CN1CCSC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 22.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(thiazolidin-3-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 235, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(thiazolidin-3-yl)acetamido)propanamide (9.3 mg, 22.8%). MS (EI) for C27H28FN3O4S. found 510.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12][CH:13]=[CH2:14]>[Pd].CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12][CH2:13][CH3:14]
Reactant: C=CCc1ccc(OC)cc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc(OC)cc1C(=O)OC
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To an ambient temperature suspension of 10% palladium on carbon (245 mg) in MeOH (5 mL) is added a solution of 2-Allyl-5-methoxy-benzoic acid methyl ester (440 mg, 2.13 mmol) in MeOH (5 mL) in one portion. The reaction is placed under an atmosphere of hydrogen gas and is stirred overnight. The reaction mixture is filtered through Celite® and concentrated to yield the title compound (361 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H, J=3.1 Hz), 7.15 (d, 1H, J=8.4 Hz), 6.97 (dd, 1H, J=8.6, 2.9 Hz), 3.89 (s, 3H), 3.82 (s, 3H), 2.88-2.82 (m, 2H), 1.65-1.53 (m, 2H), 0.95 (t, 3H, J=7.5 Hz).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.Cl.N([O-])=O.[Na+].[F:18][B-](F)(F)F.[Na+]>C(OC)(C)(C)C.C(OCC)C>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][CH:2]=[C:3]2[F:18])=[CH:8][CH:7]=1
Reactant: Nc1ccc2ccc(Br)cc2c1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Fc1cccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A solution of the product from Step A (5 g, 21 mmol) in methyl tert-butyl ether (20 ml) was treated with a solution of hydrogen chloride in diethyl ether (16.9 ml, 2 M) and the resulting mixture was stirred at room temperature. After 30 minutes, solids had precipitated and were filtered and washed with methyl tert-butyl ether. These solids were added to 6 M HCl (57.7 ml) and the resulting suspension was cooled to 0° C. Sodium nitrite (4.7 g, 70 mmol) followed by sodium tetrafluoroborate (7.4 g, 70 mmol) were added portionwise keeping the temperature at 0° C. The mixture was stirred at 0° C. for 30 minutes, then filtered. The filtrate was washed with ice cold water and extracted with ice cold methyl tert-butyl ether to give 7-bromo-1-fluoronaphthalene (4 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=1.8 Hz, 1H), 7.97 (dd, J=9.0, 1.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.7, 2.1 Hz, 1H), 7.55 (td, J=7.8, 5.4 Hz, 1H), 7.39 (ddd, J=10.8, 7.8, 0.9 Hz, 1H).