Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:9][OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:11](C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC(OC)=CC=1.O>N1C=CC=CC=1>[OH:10][CH2:9][CH:2]([O:1][CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCCCCC(O)CO
Solvent: O
Solvent: c1ccncc1
Product: C=CCCCCC(CO)OC
Reaction time: 48 h
Yield: 45.8 %

Procedure:
A mixture of 45 g of 7,8-dihydroxy-1-octene and 101.2 g of p-anisylchlorodiphenylmethane in 200 ml of pyridine was allowed to stand at 10° C. for 48 hours. The mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was dissolved in 300 ml of dimethylformamide containing 83.1 ml of methyl iodide and this solution was added dropwise to a suspension of 17.75 g of 60t sodium hydride in 500 ml of dimethylformamide over a 2 hour period. After stirring an additional 13 hours the mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was dissolved in 400 ml of methanol and stirred with 35 g of Amberlyst 15 resin. The solution was filtered and solvent was removed. The residue was purified by chromatography giving 22.6 g of 8-hydroxy-7-methoxy-1-octene as an oil.
Reaction SMILES: C1(COC(=O)[NH:10][C@H:11]([CH2:16][O:17][CH2:18][C:19]([NH2:21])=[O:20])[CH2:12][CH:13]([CH3:15])[CH3:14])C=CC=CC=1.[H][H].[C:25]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>[Pd].CO>[NH2:21][C:19](=[O:20])[CH2:18][O:17][CH2:16][CH:11]([NH:10][C:37]([CH:36]1[CH2:40][CH2:41][CH2:42][N:35]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:39])[CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)C[C@@H](COCC(N)=O)NC(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CO
Product: CC(C)CC(COCC(N)=O)NC(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
A stirred suspension of 1.58 g (0.0051 mol) of (S)-phenylmethyl-[1-[(2 amino-2-oxoethoxy)methyl]-3-methylbutyl]carbamate and 0.3 g of 20% palladium on carbon in a 100 ml of methanol is exposed to hydrogen gas for 15 minutes, the suspension is purged with nitrogen gas, filtered, and the solvent evaporated in vacuo at 30° C. The residue is dissolved in 100 ml of dichloromethane, the solution is cooled to 0° C. and 1.3 g (0.0051 mol) of carbobenzyloxyproline, 0.78 g (0.0051 mol) of 1-hyroxybenzotriazole and 1.1 g (0.0051 mol) of dicyclohexylcarbodiimide are added. The mixture is allowed to reach room temperature and stirred for 14 hours, filtered, the solvent evaporated in vacuo and the residue dissolved in 200 ml of dichloromethane and washed successively with a 5% aqueous solution of sodium carbonate, 2×200 ml, 10% aqueous solution of citric acid, 2×200 ml and a saturated aqueous solution of sodium chloride, 2×200 ml. The dichloromethane layer is separated, dried over sodium sulfate, evaporated in vacuo and the residue purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give [S-(R*,R*)]-phenylmethyl 2[[[1-[(2-amino-2-oxoethoxy)methyl]-3-methylbutyl]amino]carbonyl]-1-pyrrolidinecarboxylate, 1.1 g; mp 146°-148°; [α]D25 -55.3° (c 1.31, methanol).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1>O1CCCC1>[C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[N:11]=1)#[N:17]
Reactant: CN(C)CCS
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCSc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
2-Dimethylaminoethanethiol (0.71 g, 5.0 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.44 g, 11.0 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (0.70 g, 5.0 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (0.49 g, 47%). IR (KBr): 2233, 1576, 1549, 1456, 1425, 1143, 794 cm−1. 1H-NMR (CDCl3) δ: 2.32 (6H, s), 2.63 (2H, t, J=7.0 Hz), 3.33 (2H, t, J=7.1 Hz), 7.33-7.36 (2H, m), 7.55 (1H, t, J=7.9 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:40])([O:4][C:5]([NH:7][C:8]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:39])[NH:25][CH:26]([C:35]([O:37]C)=[O:36])[O:27][Si:28]([CH3:34])([CH3:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:6])[CH3:3].[OH-].[Na+].O.Cl>COCCOC.ClCCl>[CH3:15][C:13]([CH3:16])([O:12][C:10]([NH:9][C:8]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:39])[NH:25][CH:26]([C:35]([OH:37])=[O:36])[O:27][Si:28]([CH3:33])([CH3:34])[C:29]([CH3:31])([CH3:30])[CH3:32])=[N:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:40])=[O:6])=[O:11])[CH3:14]
Reactant: COC(=O)C(NC(=O)CCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NCCCCCCC(=O)NC(O[Si](C)(C)C(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
1.73 g (2.94.10-3 mol) of 3-[[(1,1-dimethylethoxy)carbonyl]amino]-13-(methoxycarbonyl)-15,15,16,16-tetramethyl-11-oxo-14-oxa-2,4,12-triaza-15-silaheptadec-2-enoic acid, 1,1-dimethylethyl ester are dissolved in 4 ml of 1,2-dimethoxyethane, and 4 ml of molar aqueous sodium hydroxide solution are added. The reaction mixture is stirred for 10 minutes at room temperature, 20 ml of water and 20 ml of dichloromethane are then added and the mixture is acidified to pH 2 with 1N hydrochloric acid, with thorough stirring. After separation of the organic phase, the aqueous phase is extracted with 3 times 25 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated under reduced pressure to give 1.68 g of the expected product in the form of a colorless oil (quantitative yield).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[C:9](C)=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.ClO[C:22](C)(C)[CH3:23].BrBr.C(Cl)(Cl)(Cl)[Cl:29]>C(O)(=O)C>[Cl:29][C:8]1[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6][N:5]([CH:4]([CH2:17][CH2:22][CH3:23])[C:3]([N:2]([CH3:1])[CH3:19])=[O:18])[CH:9]=1
Reactant: Cc1cc(-c2ccccc2)nn1C(C)C(=O)N(C)C
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OCl
Agent: BrBr
Solvent: CC(=O)O
Product: CCCC(C(=O)N(C)C)n1cc(Cl)c(-c2ccccc2)n1

Procedure:
Following the procedure of Example 108, but substituting N,N-dimethyl-3-phenyl-α-propylpyrazole-1-acetamide for N,N,α,5-tetramethyl-3-phenylpyrazole-1-acetamide, tert-butyl hypochlorite for bromine, and carbon tetrachloride for acetic acid as the reaction solvent, there was obtained 4-chloro-N,N-dimethyl-3-phenyl-α-propylpyrazole-1-acetamide having a melting point of 85°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Cl:10][C:11]1[NH:12][C:13]2[C:18]([C:19]=1[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[CH:17][CH:16]=[CH:15][CH:14]=2>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:21])=[O:22])=[C:11]2[Cl:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)c1c(Cl)[nH]c2ccccc12
Reactant: ClCc1ccc(Cl)cc1
Product: O=S(=O)(c1ccccc1)c1c(Cl)n(Cc2ccc(Cl)cc2)c2ccccc12
Reaction time: 4 h

Procedure:
This compound was prepared in the same manner as described in Example 17 except that following the addition of 4-chlorobenzylchloride to the anion of 2-chloro-3-phenylsulfonylindole, the reaction mixture was stirred at 90° for 4 hours. The crude product was crystallized from dichloromethane-hexane to give the product.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[C:6]2[C:7]([C:13]3[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1)=O.[CH2:22]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][O:11][C:10]1[N:5]2[N:4]=[C:3]([CH:1]=[CH2:22])[CH:21]=[C:6]2[C:7]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C=O)nn12
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=Cc1cc2c(C3=NNC(=O)CC3C)ccc(OC)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.71 mol/L n-butyl lithium-hexane solution (0.52 mL) was added dropwise to a solution of methyltriphenylphosphonium bromide (499 mg) in THE (5 mL) at 0° C. The mixture was stirred at room temperature for 30 min. The compound of Example 237 (80.0 mg) in THF (5 mL) was then added dropwise at 0° C. and the mixture was further stirred at room temperature for 2 hours. Subsequently, the reaction was quenched by adding a saturated aqueous solution of ammonium chloride and the reaction mixture was extracted with ethyl acetate (50 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purification by silica gel column chromatography (hexane:ethyl acetate=1:2) and recrystallization (ethyl acetate-hexane) afforded the title compound as a pale yellow powder (7.1 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH3:16])[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].ClC(Cl)(Cl)C(=N)O[C:23]([CH3:26])([CH3:25])[CH3:24].C1CCCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]([F:17])([F:18])[CH2:3][CH:4]([CH3:16])[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:6]([O:8][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7]
Reactant: Cc1ccc(C(C(=O)O)C(C)CC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C(C)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 3.79 g (14.5 mmol) of 5,5,5-trifluoro-3-methyl-2-(4-methylphenyl)pentanoic acid were dissolved in 60 ml of THF at room temperature, and 27 μl (0.22 mmol) of a 1 M boron trifluoride/diethyl ether complex solution were added. 3.828 g (17.48 mmol) of tert-butyl 2,2,2-trichloroethanimidoate were then metered in a little at a time, and the mixture was stirred at room temperature overnight. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 2:1), 2 g of solid sodium bicarbonate were added with vigorous stirring of the reaction solution. The reaction mixture was then filtered, and the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 5:1). This gave 3.25 g (10.27 mmol, 71% of theory) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH3:27])[CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:19]([CH3:18])[CH:20]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: Cc1ccc(CN)cc1C
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-n3cccn3)c2C#N)cc1C

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile and 3,4-dimethylbenzylamine in DME. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16]([OH:18])=O)[CH2:6]1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:21]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16](=[O:18])[NH:19][C:20]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:21]=2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Reactant: C=CCOC(=O)c1c(C)cccc1N
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1c(C)cccc1NC(=O)[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCC=C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine (2.3 g, 8.6 mM), allyl 2-amino-6-methylbenzoate (1.5 g, 7.8 mM), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.5 g, 10 mM) were dissolved in toluene (30 ml) and stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with a 2M aqueous solution of HCl (3 by 30 ml), water, a saturated aqueous solution of NaHCO3, and brine. Drying over MgSO4 and evaporation of the solvent gave (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-allyloxycarbonyl-3-methylphenylcarbamoyl)pyrrolidine as a gum (3.4 g, 97%) which was used without further purification.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:50][C:45]2[CH:46]=[CH:47][CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:50][C@@H:45]5[CH2:46][CH2:47][CH2:48][NH:49][CH2:44]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)N[C@@H]4CCCNC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-Boc-3-aminopiperidine. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC and basified using sodium bicarbonate solution to give free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.33 (m, 2 H) 1.30-1.80 (m, 7 H) 1.81-2.02 (m, 4 H) 2.31-2.45 (m, 2 H) 2.81 (d, J=12.63 Hz, 1 H) 2.97 (d, J=8.08 Hz, 1 H) 3.29 (s, 3 H) 3.71-3.90 (m, 3 H) 3.94 (s, 3 H) 4.89 (d, J=8.59 Hz, 1 H) 5.32-5.45 (m, 2 H) 6.01 (ddd, J=17.56, 12.76, 10.86 Hz, 1 H) 7.41-7.53 (m, 2 H) 7.82 (s, 1 H) 8.00 (d, J=7.83 Hz, 1 H) 8.12 (s, 1 H) 8.31 (d, J=8.08 Hz, 1 H). [M+H] calc'd for C28H36FN7O3, 538; found 538.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:20][O:21][CH3:22])([CH3:19])[O:4][C:5]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=2[C:7]=1[C:8](=[S:11])[NH:9][CH3:10].O1CCCC1.[BH4-].[Na+]>CO>[CH3:10][NH:9][C:8]([CH:7]1[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]([CH2:20][O:21][CH3:22])([CH3:19])[CH:2]1[OH:1])=[S:11]
Reactant: CNC(=S)C1=C(O)C(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(C)(COC)C1O
Yield: 39 %

Procedure:
To a mixture of 5.1 g of 3-hydroxy-2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 75 ml of tetrahydrofuran and 125 ml of methanol was added 3.0 g of sodium borohydride (NaBH4). The mixture was stirred under ice-cooling for 2 hours and subsequently stirred at room temperature for 24 hours. The reaction solution was vacuum-distilled and water was added to it and the resultant solution was extracted with methylene chloride. After an organic layer was washed with water and dried, the solvent was distilled to obtain 2 g of N-methyl-3,4-dihydro-3-hydroxy-2-methoxymethyl-2-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide. Subsequently, to 1 g of the obtained benzopyran derivative were added 1.17 g of p-toluenesulfonyl chloride and 25 ml of pyridine. The resultant mixture was refluxed with heating for 1 hour and the solvent was distilled. Ice water was added to the residue and it was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, hexane:AcOEt=1:1) to obtain 680 mg of 2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 128°-130° C.
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCC(O)[C@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in Et2O (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in Et2O, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was stirred at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was recooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil. Yield: 1.19 g (73%). (65% de 3R,4S: 35% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.46+0.69 (t & m, 6H, J=7.34 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.13-1.29 (m, 4H, —NHCH(CH2CH3) CH(CH2CH3)OH), 2.17 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.55 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.20-3.39 (m, 1H, —NHCH(CH2CH3)CHCH2CH3)OH), 4.29 & 4.39 (2×d, 1H, J=4.74 & 5.53 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Ph).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=2)[CH:2]=1.[NH2:16][C@@H:17]([CH3:33])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=2)=[N:20]1>CN(C)C=O>[Cl:32][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:13]([C:10]3[N:11]=[CH:12][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)=[O:15])[CH3:33])[N:20]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccc(-c2cccnc2)cn1
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccc(-c2cccnc2)cn1
Yield: 45.2 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 5-(pyridin-3-yl)picolinic acid (130 mg, 0.549 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (150 mg, 0.577 mmol) using N,N-dimethyl formamide as the solvent. The product was purified by flash chromatography. Yield 45.2%. 1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 4.38 (dd, 1H), 4.46 (dd, 1H), 4.49-4.59 (m, 1H), 6.96 (d, 1H), 7.59 (q, 1H), 7.87 (d, 1H), 7.97 (dd, 1H), 8.01 (d, 1H), 8.06-8.12 (m, 2H), 8.21-8.26 (m, 1H), 8.35 (dd, 1H), 8.69 (dd, 1H), 9.01-9.07 (m, 2H), 9.14 (d, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23]C)[CH2:6][CH:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:8]1.B(Br)(Br)[Br:26].CO>C(Cl)Cl>[BrH:26].[OH:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[OH:23])[CH2:6][CH:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:8]1
Reactant: BrB(Br)Br
Reactant: COc1ccc(CC2CCC(CCc3ccccc3)N2)cc1OC
Solvent: ClCCl
Solvent: CO
Product: Br
Product: Oc1ccc(CC2CCC(CCc3ccccc3)N2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (-70° C.) solution of 15.1 g (0.057 mole) of 2-(3'4'-dimethoxybenzyl)-5-(2-phenylethyl)pyrrolidine in 1 L of methylene chloride was added dropwise 55.1 g (0.22 mole) of boron tribromide. After the addition the reaction mixture was gradually warmed up to room temperature over a period of 2 h. The mixture was cooled again to -70° C. and 300 ml. of methanol was carefully added. Solvent was removed in vacuo. An additional 100 ml of methanol was added and removed in vacuo. The gummy dark residue was boiled in ethyl acetate and decanted, then triturated with ethyl acetate and left overnight to give a solid. This was recrystallized twice from acetonitrile to give 6 g. m.p. 149°-151° C.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6](C(O)=O)[CH:5]=1)([O-:3])=[O:2].C[N:13]([C:15]([O:19]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.N[CH2:45][CH:46]1[CH2:48][CH2:47]1>CN(C=O)C>[N+:1]([C:4]1[NH:8][N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:46]1[CH:48]([CH2:47][C:15]([NH2:13])=[O:19])[CH2:45]1
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: NCC1CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CC1CC1
Product: O=[N+]([O-])c1ccn[nH]1
Reaction time: 0.17 h

Procedure:
7.5 g of 5-nitro-1H-pyrazole-3-carboxylic acid were dissolved in 70 ml of DMF. 19.9 g of HATU and 9.6 g of triethylamine are added at RT and, after stirring for 10 minutes, 5.1 g of aminomethylcyclopropane hydrochloride are added, and the mixture is stirred at RT overnight. After aqueous workup, the crude product is purified by column chromatography (silica gel, methanol:DCM=1:30).
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18](O)[CH2:17][CH2:16]2)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2].CS(Cl)(=O)=O.C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]2[C:19]([CH:18]=[CH:17][CH2:16]2)=[CH:20][CH:21]=1)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CC=C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
In 5 ml of pyridine was dissolved 1.0 g of 1-acetoxy-1-[(1-hydroxy)indan-5-yl]-2-[2-(N,N-dimethylamino)ethoxy]ethane. To the solution was added 0.3 ml of methanesulfonyl chloride at room temperature. The resulting mixture was stirred at the same temperature overnight. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The resulting mixture was adjusted to pH 8.5 with potassium carbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatograph (eluant: chloroform/methanol=10/1) to obtain 80 mg of oily 1-acetoxy-1-(1H-inden-6-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethane (compound No. 297).