Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1>CO.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)c1
Agent: [Pd]
Solvent: CO
Product: Cn1cnc(-c2cc(Oc3ccc(N)nc3)ccn2)c1
Yield: 90.5 %

Procedure:
A solution of 2-(1-methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.61 g, 5.42 mmol) in MeOH (30 mL) was treated with 10% Pd/C (50% w/w water, 0.576 g, 0.542 mmol) and hydrogenated (50 psi) overnight. The solids were removed via filtration through diatomaceous earth, washed with warm MeOH and the filtrate was concentrated to dryness to afford 5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.311 g, 91%). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1 H), 7.81 (d, J=2.9 Hz, 1 H), 7.65 (d, J=1.3 Hz, 1 H), 7.58 (s, 1 H), 7.29 (dd, J=8.9, 3.0 Hz, 1 H), 7.19 (d, J=2.6 Hz, 1 H), 6.73 (dd, J=5.7, 2.6 Hz, 1 H), 6.52 (d, J=8.9 Hz, 1 H), 6.03 (s, 2 H), 3.67 (s, 3 H); MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].[CH:32]([NH2:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: CC(C)N
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CSc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 97322.8 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (150 mg, 0.34 mmol) in CH2Cl2 (10 mL) were added isopropylamine (0.087 mL, 1.02 mmol), HATU (135 mg, 0.355 mmol) and diisopropyl ethyl amine (0.2 mL, 1.15 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and shaked. The layers were separated and the organic layer was washed with brine (75 mL), dried over Na2SO4, filtered and concentrated. Flash chromatography then provided the title compound as a white solid 160 g (97%). LC-MS m/z 484 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[Cl-].[NH4+:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH2:28])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to ammonium chloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 386 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>CN1C(=O)CCC1>[NH2:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:15][CH2:16]2)[CH:3]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Product: CSc1nc(N)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 49.8 %

Procedure:
TEA (0.243 ml, 1.74 mmol) and 6-chloro-2-(methylthio)pyrimidin-4-amine (0.309 g, 1.74 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.35 g, 1.74 mmol) in NMP (4 ml). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 90 minutes. The mixture was partitioned between water and EtOAc and washed (×2) with water. The organic phase was dried over magnesium sulphate and concentrated to give the title compound (0.294 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[CH3:53][C:54]1[O:58][N:57]=[C:56]([C:59](Cl)=[O:60])[CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:59]([C:56]2[CH:55]=[C:54]([CH3:53])[O:58][N:57]=2)=[O:60])[CH2:25]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)no1
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 87% yield. LCMS for C27H26ClN8O3 (M+H)+: m/z=545.0.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[S:50][CH:49]=[N:48][CH:47]=1>>[CH3:44][C:2]([CH3:1])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:46]3[S:50][CH:49]=[N:48][CH:47]=3)[CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: Brc1cncs1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C(=O)O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1cccc(-c2cncs2)c1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 5-bromothiazole. MS (ESI): mass calcd. for C32H28N4O3S, 548.19; m/z found, 549.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.71 (d, J=8.4, 1H), 8.32 (s, 1H), 8.24 (d, J=8.7, 1H), 8.13 (d, J=8.1, 1H), 7.94 (t, J=7.7, 1H), 7.88 (d, J=8.5, 1H), 7.80-7.69 (m, 2H), 7.66-7.61 (m, 2H), 7.48-7.36 (m, 2H), 7.32 (dd, J=9.1, 2.3, 1H), 7.16 (d, J=7.6, 1H), 5.85 (s, 2H), 5.64 (s, 2H), 3.56 (s, 2H), 1.32 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[F:36][C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:40]4[CH2:39][CH:38]=[C:37]([F:36])[CH2:42][CH2:41]4)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: FC1=CCNCC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC=C(F)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 35 (60 mg) in 1-methyl-2-pyrrolidinone (3 mL) is added N,N-diisopropylethylamine (0.075 mL) and 4-fluoro-1,2,3,6-tetrahydropyridine hydrochloride from Preparation No. 38 (119 mg). The reaction mixture is stirred at room temperature overnight and then heated at 60° C. for 4 hrs. The mixture is cooled to room temperature and poured into water to precipitate the product. The crude solid is adsorbed onto silica and purified by chromatography (eluent 100% CH2Cl2 (1 L), 0.25% MeOH in CH2Cl2 (1 L), 0.5% MeOH in CH2Cl2 (1 L), 0.75% MeOH in CH2Cl2 (1 L), 1% MeOH in CH2Cl2 (1 L), 1.25% MeOH in CH2Cl2 (1 L), 1.5% MeOH in CH2Cl2 (2 L)). Fractions homogenous by TLC are combined and concentrated to afford 32.2 mg (46%) of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1.C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:5]3[N:4]=[C:3]([N:9]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:2]([Br:1])=[CH:7][N:6]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1ncc(Br)c(N(c2ccccc2)C2CCCCC2)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)c(N(c4ccccc4)C4CCCCC4)n3)cc2)CC1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
Compound 37 (0.42 g, 1.15 mmol) and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 2.30 mmol) were dissolved in dioxane (2 mL), and this mixture was heated at 100° C. for 24 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. This mixture was washed with water and brine. The organic layer was dried with sodium sulfate and purified by flash chromatography (ethyl acetate/hexane) to give compound 38 as a yellow solid (0.23 g, 33%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.18 (1 H, s), 7.97 (1 H, s), 7.55 (2 H, d, J=10 Hz), 7.37 (2 H, m), 7.31 (1 H, m), 7.12 (2 H, m), 6.89 (2 H, d, J=10 Hz), 4.68 (1 H, m), 3.44 (4 H, m), 3.00 (4 H, m), 1.91 (2 H, d, J=10 Hz), 1.72 (2 H, d, J=10 Hz), 1.57 (1 H, d, J=10 Hz), 1.41 (9 H, s), 1.35 (2 H, m), 1.14 (2 H, m), 0.92 (1 H, m); LCMS-ESI (POS), M/Z, M+1: Found 609.2, Calculated 607.2/609.2.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:8][C:9]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=1[CH:11]=O.N1CCCCC1.C(O)(=O)C>C(O)(C)C>[Cl:8][C:9]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=1[CH:11]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([NH2:7])=[O:6]
Reactant: CC(=O)CC(N)=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(Cl)cc1Cl)C(N)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of acetoacetamide (5.05 g, 50 mmol), 2,4-di-chlorobenzaldehyde (9.20 g, 52 mmole), piperidine (170 mg, 2 mmol) and acetic acid (120 mg, 2 mmol) in isopropanol (50 mL) was stirred at room temperature for 14 h. The precipitation was collected and rinsed with an additional isopropanol (20 mL). After drying in vacuo, 2-(2,4-dichlorobenzylidene)-3-oxobutanamide was obtained as a white solid (6.3g, 49%).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:50][NH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:52]([N:51]([CH3:50])[C:10]([C@@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: C=CCCCCNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a cold solution of cis-N-Boc-4-hydroxy-L-proline (10 g, 1 eq.), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU 15.5 g, 1.12 eq.) and N-methylhex-5-en-1-amine tosylate salt 32a (13.6 g, 1.1 eq.), which was prepared according to Scheme 13 as described herein, in DMF (80 mL) containing DIPEA (29.4 mL, 3.9 eq.) was added dropwise under nitrogen at 0° C. The reaction mixture was stirred overnight at room temperature, and then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 48 as a rose powder in 95% yield. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.29-1.3 (m, 9H), 1.33-1.55 (m, 4H), 1.70-1.80 (m, 1H), 1.97-2.12 (m, 3H), 2.77-2.97 (m, 3H), 3.15-3.40 (m, 4H), 4.22 (br s, 1H), 4.50-4.62 (m, 1H), 4.90-5.04 (m, 3H), 5.71-5.83 (m, 1H); MS (ESI+): m/z=327 (MH+).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].CCN(C(C)C)C(C)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1.[C:50](N1C2C=CC=CC=2N=N1)(=[NH:52])[NH2:51]>CN(C=O)C>[C:39]1([CH3:49])[CH:40]=[CH:41][C:42]([S:45]([OH:48])(=[O:46])=[O:47])=[CH:43][CH:44]=1.[C:50]([N:7]1[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]1)(=[NH:51])[NH2:52]
Reactant: N=C(N)n1nnc2ccccc21
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(C(=N)N)CC1
Reaction time: 24 h

Procedure:
Morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride (0.2 g, 0.47 mmol) was dissolved in 3 mL of DMF and 2 equiv of Hunig's base was added followed by 1-carbamimidoyl-1,2,3-benztriazole p-toluenesulfonate (0.16 g, 0.47 mmol). The reaction was stirred 24 hours at which time the solvent was removed in vacuo. The resulting paste was purified by preparative HPLC to give the title compound; MS, m/z 434, M+1-p-toluene sulfonate).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46]I>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][CH3:46])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CI
Product: COCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(COCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with methyl iodide there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 643 (M+NH4)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: ClCCCCBr
Reactant: CCC1C(=O)Nc2ccc(F)cc21
Product: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2
Reactant: Clc1ccc2[nH]ccc2c1
Agent: c1ccc2[nH]ccc2c1
Product: Clc1ccc2c(c1)CCN2
Yield: 42.8 %

Procedure:
In another comparison example in which 5% ruthenium-carbon catalyst without a nitrocompound as the hydrogen acceptor was used, a mixture of 307.2 g (2 moles) of 5-chloro-indoline, 500 ml of xylene and 15 g of 5% ruthenium-carbon catalyst was refluxed with stirring for 7 hours and the mixture was then cooled and vacuum filtered. 800 ml of dilute hydrochloric acid formed from 130 ml of concentrated hydrochloric acid and 670 ml of water was added in 3 equal portions to the filtrate. The organic phase was dried over potassium carbonate and was evaporated to dryness under reduced pressure. The residue was subjected to fractional distillation to obtain a first fraction of 146 g of a product with a boiling point of 92° to 98° C. at 0.03 mbar and a melting point of 57° to 60° C. and a residue of 12 g (4% yield). Gas chromatography of the first fraction indicated that it was a mixture of 35% of indole and 65% of 5-chloro-indole. The acid extract was neutralized to recover 132 g (42.8% yield) of 5-chloro-indoline.
Reaction SMILES: [H-].[Na+].C1COCC1.[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCCC.CCOC(C)=O.O>[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25]
Reactant: Brc1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Temperature: 25 °C
Yield: 100 %

Procedure:
Sodium hydride (2.8 g, 60%, 70.4 mmol) was washed with heptane to remove the mineral oil prior reaction. The sodium hydride was mixed with THF (250 mL) and cooled on an ice bath before 4-bromoindole (4.6 g, 23.5 mmol) was added. The reaction mixture was stirred for 15 minutes before benzenesulfonyl chloride (6.22 g, 35.2 mmol) was added. The reaction mixture was stirred at RT ON. Ice and water was added followed by EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc twice. The combined organic phases were dried (MgSO4) before the solvent was evaporated. The obtained crude product was pure enough to be used in the next step. Got 8.52 g of an oil which solidified on standing, yield 100%. MS (ESI+) for C14H10BrNO2S m/z 336 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1([OH:21])C2C(=CC=CC=2)C=CC=1>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[OH:21]
Reactant: Oc1cccc2ccccc12
Reactant: c1ccc2ccccc2c1
Product: Oc1ccc2ccccc2c1

Procedure:
A further selective hydroxylation reaction was carried out with the sol-gel-embedded CYP BM-3 on the substrate naphthalene. 77% of the precursor were hydroxylated. The main product obtained was 1-naphthol (85%), and 2-naphthol was obtained as by-product (15%) (detected by gas chromatography).
Reaction SMILES: [Zn](CC)[CH2:2]C.C(I)I.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH:18]=2)[CH:13]=[CH:14][C:15]=1[Cl:16]>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]23[CH2:2][CH:18]2[CH:19]([OH:22])[CH2:20][CH2:21]3)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: OC1C=C(c2ccc(Cl)c(Cl)c2)CC1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: OC1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Reaction time: 0.08 h
Yield: 56.3 %

Procedure:
To an Et2Zn solution (1.0M in hexane; 14 mL, 14 mmol) cooled to 0° C., a solution of CH2I2 (1.13 mL, 14 mmol) in CH2Cl2 (10 mL) was added. This was stirred for 5 min, then a solution of 3-(3,4-dichlorophenyl)cyclopent-2-en-1-ol (0.5 g, 2.19 mmol) in CH2Cl2 (50 mL) was added dropwise. The reaction mixture was stirred overnight then quenched with saturated aqueous NH4Cl. The reaction mixture was extracted with CH2Cl2 (3×). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the crude material by silica gel chromatography using 10-30% EtOAc/Heptane as the eluting solvent gave the target compound (0.3 g, 64%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.76-0.85 (m, 1 H) 1.20-1.33 (m, 2 H) 1.65-1.77 (broad, 1 H) 1.83-1.90 (m, 1 H) 1.93-2.17 (m, 3 H) 4.64-4.73 (m, 1 H) 6.93-6.97 (m, 1 H) 7.22 (d, 1 H) 7.29-7.34 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>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.[OH-].[Na+]>[NH2:27][C:28]1[CH:33]=[C:32]([C:4]2[CH:5]=[C:6]3[C:11]([CH2:10][CH2:9][CH:8]([N:12]([CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH3:15])[CH2:7]3)=[CH:2][CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(Br)cc2C1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(-c3cccc(N)c3)cc2C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A 1 mL solution of (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amine (25 mmole in DMA) was added to a tube containing 2-3 mg Pd(PPh3)4 catalyst followed by 120 μL of a solution of 3-amino phenyl boronic acid (30 mmole in DMA), and 200 μL 1N aq. NaOH. The solution was shaken at 80° C. for 4 h, concentrated, and purified by chromatography to yield [7-(3-amino-phenyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amine 112[M+H]+=456.