Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])[CH3:46].C(N(CC)CC)C>ClCCl>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH:51][C:26]([C:25]1[CH:24]=[N:23][C:22]([NH:21][C@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=3)=[N:9][CH:10]=2)[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:30][CH:29]=1)=[O:28])[CH3:46]
Reactant: CCOC(=O)CCN
Reactant: CC(C)C[C@H](Nc1ccc(C(=O)O)cn1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-{(S)-3-Methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-nicotinic acid (31.1 g wet with ethyl acetate, theoretical 65.8 mmol) was dissolved in dichloromethane (270 mL). 1-Hydroxybenotriazole hydrate (15.1 g, 98.7 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (18.9 g, 98.7 mmol). beta-Alanine ethyl ester hydrochloride (12.1 g, 79.0 mmol) was added and the reaction was placed in an ice bath. When only slightly cool, triethylamine (18.3 mL, 132 mmol) was added over 3 min. The bath was then removed and the reaction was stirred at room temperature as a solution. At 16 h, most of the dichloromethane was rotovapped off. The residue was partitioned between ethyl acetate and sat. NH4Cl. The aqueous was extracted with additional ethyl acetate and the combined organics were washed with sat. NaHCO3 two times. The first aqueous was back extracted with ethyl acetate to remove a small amount of product. The combined organics were washed with brine and dried over MgSO4. The material was purified by silica gel flash chromatography (ethyl acetate/heptane) and then further purified by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 21 mm×250 mm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 65 ml/min. The purified material was taken up in ethyl acetate, filtered through a course frit and concentrated in vacuo to give 3-[(6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid ethyl ester with ethyl acetate (29.2 g) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.83 (s, 2 H) 8.54 (d, J=8.0 Hz, 2 H) 8.46 (d, J=2.0 Hz, 1 H) 7.81 (dd, J=8.7, 2.2 Hz, 1 H) 7.73 (d, J=8.4 Hz, 2 H) 6.64 (t, J=5.8 Hz, 1 H) 6.36 (d, J=8.6 Hz, 1 H) 5.13 (d, J=6.7 Hz, 1 H) 4.97-5.08 (m, 1 H) 4.09-4.21 (m, 2 H) 3.68 (q, J=5.9 Hz, 2 H) 2.60 (t, J=5.9 Hz, 2 H) 1.81-1.95 (m, 1 H) 1.67-1.81 (m, 2 H) 1.26 (t, J=7.1 Hz, 3 H) 1.03 (d, J=6.1 Hz, 3 H) 1.00 (d, J=6.1 Hz, 3 H); MS (M+1): 530.2. Analytical chiral SFC: Column—Chiralcel OJ-H. Dimensions: 4.6 mm×25 cm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 2.5 mL/min. Retention time: 5.18 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH:11]=2)[CH2:6]1.NN.Cl>C(O)(C)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:11]=2)[CH2:6]1
Reactant: COC(=O)CC1CCc2cc(OCCCN3C(=O)c4ccccc4C3=O)ccc2C1
Agent: Cl
Agent: NN
Solvent: CC(C)O
Product: COC(=O)CC1CCc2cc(OCCCN)ccc2C1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a suspension of {6-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic acid methyl ester, (17.7 g) in isopropyl alcohol (350 mL) heated at 55° C. was added hydrazine (3 mL). The mixture was heated to reflux for 1.5 h, then the reaction mixture was allowed to stand at room temperature overnight. Concentrated HCl (7.8 mL) was added, the mixture was stirred for 10 minutes, and filtered. The white solid was washed with isopropyl alcohol. The filtrate was concentrated under reduced pressure and applied to a silica gel column. Elution with 2% NH4OH/10% MeOH/CH2Cl2 afforded the product of the example as a golden oil which solidified on standing (8.0 g). NMR (300 MHz, CDCl3) δ6.95 (d, J=8.34 Hz, 1H), 6.67 (dd, J=8.30, 2.55 Hz, 1H), 6.62 (d, J=2.16 Hz, 1H), 4.01 (t, J=6.07 Hz, 2H), 3.69 (s, 3H), 2.93 (broad s, 2H), 2.86-2.77 (m, 3H), 2.46-2.36 (m, 3H), 2.26-2.18 (m, 1H), 2.12-1.98 (broad s, 2H), 1.93 (m, 3H), 1.51-1.38 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[C:8]([CH3:38])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(Cl)cc3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 180 mg. HPLC-MS: m/z: 538.0 (M+); Rt: 1.84 min. δH(400 MHz; CDCl3) 2.27 (s, 3H), 3.15-3.30 (m, 2H), 3.45 (d, 2H), 3.99-4.06 (m, 2H), 4.13-4.22 (m, 4H), 4.73 (s, 2H), 4.96 (s, 2H), 6.57-6.60 (m, 1H), 6.74 (d, 1H), 6.76-6.81 (m, 2H), 7.25-7.31 (m, 4H), 7.32-7.36 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl>[NH2:26][C:25]1[CH:27]=[CH:28][C:22]([CH2:21][CH2:20][NH:19][S:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
47.5 ml of triethylamine and then, in portions, 72 g of 4-chlorobenzenesulphonyl chloride, are added at ambient temperature to a solution of 46.5 g (340 mmol) of 4-(2-aminoethyl)aniline in a liter of dichloromethane. The mixture is then stirred for one night and subsequently filtered. The solid obtained is washed with water and dried using a dessicator to yield the expected product.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[CH:11]1([C:17]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1NC(=O)C1CCCCC1

Procedure:
Anthranilamide was treated with cyclohexanecarbonyl chloride and triethylamine in dichloromethane, followed by washing (10% citric acid; water; sat. sodium bicarbonate; and sat. sodium chloride) and evaporated to give a nearly quantitative yield of 2-(cyclohexylcarbonylamino)benzamide as a white solid, which was used immediately in the next step.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[Br:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][C:20]=2[NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[C:4]([OH:3])=[O:16])[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=9.46 min. MS (ESI−): mass calcd. for C24H17BrClFN4O5S, 607.84; m/z found, 605/607 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.66 (s, 1H), 8.99-8.93 (m, 2H), 8.63-8.57 (m, 1H), 8.37-8.31 (m, 1H), 8.02-7.97 (m, 2H), 7.78-7.75 (m, 1H), 7.65-7.60 (m, 1H), 7.58-7.53 (m, 1H), 7.41-7.34 (m, 1H), 7.24-7.17 (m, 1H), 6.97 (dd, J=8.3, 1.6, 1H), 5.00-4.92 (m, 1H), 3.37-3.28 (m, 1H), 3.18-3.10 (m, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[C:16](\[CH3:22])/[C:17](OCC)=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12](/[CH:15]=[C:16](\[CH3:22])/[CH2:17][OH:18])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(=C\[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1)CO
Reaction time: 0.5 h

Procedure:
To a solution of 300 mg (0.95 mmol) of enoate (19) in 2.0 mL of anhydrous tetrahydrofuran at 25° C. was added 18 mg (0.43 mmol) of lithium aluminum hydride and the resulting mixture was allowed to stir for 30 min. The reaction was quenched by the slow addition of saturated Rochelle's salt and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic extracts were washed with water and brine and then dried over MgSO4. Evaporation and flash chromatography (elution with 1:10 ethyl acetatehexane) gave 220 mg of the allyic alcohol (20). 1H NMR (300 MHz, CDCl3) δ 5.34 (d), 3.96 (d), 3.85 (m), 2.26-2.18 (m), 1.64 (d), 1.61-1.34 (m), 1.82 (s), 0.0 (s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-4-fluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=1.1 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.5, 1.5 Hz, 1H), 7.10-6.98 (m, 2H), 6.84-6.76 (m, 2H), 4.63 (t, J=5.0 Hz, 2H), 4.22 (t, J=5.0 Hz, 2H), 2.49 (s, 3H); MS (ES) m/z 329 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH:11]([F:13])[F:12])=[N:4][CH:5]=[C:6]([CH2:8][Br:9])[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[Br:9][CH2:8][C:6]1[CH:7]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)[C:3]([O:10][CH:11]([F:13])[F:12])=[N:4][CH:5]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: FC(F)Oc1ncc(CBr)cc1Br
Product: FC(F)Oc1ncc(CBr)cc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 10, using Intermediate 4 and 3-chlorophenyl boronic acid in Step 1, followed by bromination according to Step 3. [M+H]=348.17/350.15
Reaction SMILES: C(OC([N:8]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([O:19][CH2:20][CH2:21][C:22]([O:24][C@H:25]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)[CH:37]=2)[CH2:26][C:27]2[C:32]([Cl:33])=[CH:31][N+:30]([O-:34])=[CH:29][C:28]=2[Cl:35])=[O:23])=[O:18])=[CH:15][C:14]=1[O:53][CH2:54][CH:55]1[CH2:57][CH2:56]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:35][C:28]1[CH:29]=[N+:30]([O-:34])[CH:31]=[C:32]([Cl:33])[C:27]=1[CH2:26][C@@H:25]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[O:24][C:22](=[O:23])[CH2:21][CH2:20][O:19][C:17](=[O:18])[C:16]1[CH:51]=[CH:52][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:53][CH2:54][CH:55]2[CH2:56][CH2:57]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)OCCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 85.7 %

Procedure:
To a solution of (S)-4-(2-(3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.450 g, 0.523 mmol) in dry DCM (15 ml), 4M HCl in dioxane (0.654 ml, 2.62 mmol) was added. The resulting mixture was stirred at RT for 4 days. The solvent was evaporated and the residue was purified by trituration with Et2O (30 ml) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)propanoyloxy)ethyl)-pyridine 1-oxide (0.340 g, 0.448 mmol, 86% yield, MS/ESI+759.31 [MH]+, [αD]=−8.9, c=0.6, DCM).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH:14]3[N:16](C(OC(C)(C)C)=O)[CH:11]2[CH2:12][CH2:13]3)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][CH:10]2[CH2:15][CH:14]3[NH:16][CH:11]2[CH2:12][CH2:13]3)[N:5]=1
Reactant: Cc1cc(C)nc(NC2CC3CCC2N3C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(NC2CC3CCC2N3)n1

Procedure:
To the title compound of step A (125 mg, 0.4 mmol) in DCM (3 mL) was added TFA (3 mL). After starting material was consumed, the reaction was concentrated, neutralized with 5% Na2CO3 and extracted with DCM. The combined organics were dried (Na2SO4) to give the title compound that was used in subsequent reactions without further purification. MS (ESI) mass calcd. for C12H18N4, 218.2; m/z found 219.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)Cl.[C:31]([O:40][CH2:41][CH3:42])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH2:34]>ClCCl>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=1[C:31]([O:40][CH2:41][CH3:42])=[O:39])=[O:9]
Reactant: CCOC(=O)c1ccccc1N
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Under an ice-cooled condition, 332 mg (1 mmol) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl) pyridine-3-carboxylic acid was suspended in dried dichloromethane. The mixture was stirred with addition of 229 mg (1.1 mmol) of phosphorus pentachloride little by little for one hour. At -30° C., 1650 mg (10 mmol) of ethyl anthranilate was added to the reaction mixture. The reaction mixture was further stirred at room temperature for one hour. After washing with water, the reaction mixture was dried over anhydrous sodium sulfate. The thus obtained mixture was chromatographed on a silica gel column for purification, whereby 486 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[CH2:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[NH:1][C@@H:2]([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[CH2:9][C:10]([O-:11])=[O:12])[CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Reactant: O=C=Nc1cccc(Cc2ccccc2)c1
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1cccc(Cc2ccccc2)c1
Yield: 93.4 %

Procedure:
According to the method described in example S11, aminocarnitine (1.28 HBr salt, 68 mg, 0.31 mmol) was reacted with 1-benzyl-3-isocyanatobenzene (132 mg, 0.63 mmol) to yield the title compound as a white solid (107 mg, 92%). NMR (400 MHz, CD3OD) δ=ppm 7.11-7.29 (m, 8H), 6.83 (d, J=7.33 Hz, 1H), 4.58 (br. s, 1 H), 3.89 (s, 2 H), 3.71 (dd, J=13.64, 9.35 Hz, 1 H), 3.50 (d, J=13.39 Hz, 1 H), 3.17 (s, 9 H), 2.40-2.58 (m, 2 H). MS ESI [M+H]+, calcd for [C21H27N3O3+H]+ 370.46 found m/z 370.2 (100).
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[Si](C)([O:16][CH2:17][CH2:18][O:19][Si](C)(C)C)C.[C:25]1(=O)[CH2:29][CH:28]=[CH:27][CH2:26]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:16]1[C:28]2([CH2:27][CH:26]=[CH:25][CH2:29]2)[O:19][CH2:18][CH2:17]1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: O=C1CC=CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C1=CCC2(C1)OCCO2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of trimethylsilyl trifluoromethanesulfonate (CAS number 27607-77-8; 0.22 ml, 1.22 mmol) in DCM (12 ml) at −78° C. was successively added 2,2,7,7-tetramethyl-3,6-dioxa-2,7-disilaoctane (CAS number 7381-30-8; 2.51 g, 12.18 mmol) and cyclopent-3-en-1-one (CAS number 14320-37-7; 1 g, 12.18 mmol). The reaction mixture was stirred at −78° C. for 3 hours, quenched with triethylamine (2 ml, 14.35 mmol), poured into a saturated solution of sodium bicarbonate and extracted with diethyl ether. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]=[C:2]([CH2:12][CH3:13])[CH2:3][CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(OO)(=[O:16])C>C(Cl)Cl>[CH2:12]([C:2]1([CH2:1][OH:16])[CH2:3][CH2:4][C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[O:11]1)[CH3:13]
Reactant: CC(=O)OO
Reactant: C=C(CC)CCC1(O)CCOCC1
Solvent: ClCCl
Product: CCC1(CO)CCC2(CCOCC2)O1
Reaction time: 4 h
Yield: 69.2 %

Procedure:
To a stirred solution of 16.52 g of tetrahydro-4-(3-methylenepentyl)-2H-pyran-4-ol in 100 ml of methylene chloride under nitrogen was added portionwise 15.32 g of peracetic acid (with 0.40 g of anhydrous sodium acetate added). The reaction mixture was refluxed for 1 hour, allowed to set for 4 hours, diluted with 150 ml of methylene chloride, washed successively with water, twice with 25% potassium carbonate, and saturated sodium chloride, dried and filtered. The resulting solution was stripped to yield 12.42 g of the desired product as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:22][CH:23]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[S:22][CH:23]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 4-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole: MS (ES) m/z 466 (M+1).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>C1COCC1.[Zn]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)CBr
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCCC1
Yield: 95.2 %

Procedure:
To a solution of cyclohexanone (9.52 g, 97.0 mmol), a zinc powder (7.6 g, 116.4 mmol) and a small amount of iodine in THF (100 ml) was added dropwise ethyl bromoacetate (11.8 ml, 106.7 mmol) under a nitrogen atmosphere, and the mixture was heated under reflux for 5 hrs. 10% Sulfuric acid (100 ml) was carefully added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the title compound (17.2 g, 94%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: NCCCn1ccnc1
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1ccnc1

Procedure:
When 5-chloroisatoic anhydride was reacted with 1H-imidazole-1-propanamine by the procedure of Example 11, the above compound, mp 155°-157° C., was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:26])[NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COCCNC(=O)Cc1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12

Procedure:
As described in Example 1, 60 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with 2-methoxy-ethylamine to give 40 mg of {6,7-dimethoxy-4-[(2-methoxy-ethylcarbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. H1-NMR (CDCl3): δ, d 8.21 (s, 1H), 7.40 (s, 1H), 7.25 (s, 1H), 6.17 (br s, 1H), 5.74 (br s, 1H), 4.89 (d, J=4.7 Hz, 2H), 4.03 (s, 6H), 3.89 (s, 2H), 3.36 (m, 4H), 3.17 (s, 3H), 1.51 (s, 9H); MS: APCI (M+H) calc'd for C22H31N3O6+H 434.5; found 434.0.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:19][CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)/C=C/c1cccc(CBr)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution prepared with t-butyl 3-(6-hydroxymethyl-pyridin-2-yl)-trans-acrylate (trans form, 2 g) described in Reference Example 10-(1) and carbon tetrabromide (4.23 g) in methylene chloride (20 mL) at ice temperature, triphenylphosphine (2.68 g) was added in small portions, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was transferred to a separating funnel, diluted with chloroform, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=10:1) to give 2.23 g of t-butyl 3-(6-bromomethylpyridin-2-yl)-trans-acrylate as a light yellow powder.