Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.[N:15]1[C:22]([NH2:23])=[N:21][C:19]([NH2:20])=[N:18][C:16]=1[NH2:17]>>[P:2]([OH:13])([OH:9])([OH:3])=[O:1].[N:15]1[C:22]([NH2:23])=[N:21][C:19]([NH2:20])=[N:18][C:16]=1[NH2:17]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: Nc1nc(N)nc(N)n1
Product: O=P(O)(O)O

Procedure:
Under atmosphere, charged in a twin-screw extruder were 70.97 g (0.5 moles) of diphosphorus pentoxide and 126.06 g (1.0 moles) of melamine (commercial name: Chang Chun Melamine), and a bar like product was formed at the extrusion temperature of 340° C. After being cooled, the bar like product is pulverized, thereby a powdery melamine phosphate product is obtained. The thermal degradation of the powdery product at 260° C. was measured with differential thermo/thermogravimetric analyzer. The loss of weight was 0.25% by weight. The results of phosphorus content and dispersibility of the powdery melamine phosphate product were shown as in Table 1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.O.Cl.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1N(c2ccccc2)CCN1C1CCNCC1
Yield: 93.6 %

Procedure:
11.1 g of 1-(1-benzyl-4-piperidinyl)-3-phenyl-2-imidazolidinone are dissolved in 85 ml of methanol, 34 ml of water and 3.2 ml of hydrochloric acid (chemically pure), and, with the addition of 1.2 g of a 5% palladium on charcoal catalyst, hydrogenated at room temperature and under normal pressure. The calculated amount of hydrogen has been taken up after approx. 15 hours. The reaction mixture is filtered to remove the catalyst and concentrated in a water jet vacuum. The crystalline residue is treated with 2 N sodium carbonate solution and extracted with chloroform. The combined chloroform extracts are dried over sodium sulphate and concentrated in a water jet vacuum to yield 7.6 g of 1-(4-piperidinyl)-3-phenyl-2-imidazolidinone as a colourless oil which crystallises on standing; melting point 123°-124° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[Br:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH2:44])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[Br:32].CC(N(C)C)=O>C1COCC1.O.ClCCl.CO>[Br:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH:44][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[Br:32]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Nc1cc2c(Nc3ccc(Br)c(Br)c3)ncnc2cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(Br)c(Br)c3)ncnc2cn1)OCC
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
To a stirred mixture of CDI (2.74 g, 16.9 mmol) and dry THF (13 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (2.96 g, 15.1 mmol) in THF (10 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A solution of compound 225 (2.38 g, 6.02 mmol) in a mixed solvents of dry THF (7 mL) and DMA (8 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=15:1). After stirred for 4 h, the reaction mixture was poured into water (250 mL) and stirred with petroleum ether (350 mL) at room temperature for 20 min. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (200 mL). The solid was collected by suction filtration; washed with water (5×30 mL) and dried to give diethyl 2-(4-(3,4-dibromophenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (234) (3.28 g, 95%); mp 120-124° C.; 1H NMR δ [(CD3)2SO]: 10.89 (s, 1H), 10.41 (s, 1H), 9.04 (s, 1H), 8.88 (s, 1H), 8.67 (s, 1 H), 8.34 (d, J=2.5 Hz, 1H), 7.87 (dd, J=8.8, 2.5 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 4.17-4.03 (m, 4H), 3.32 (d, J=21.6 Hz, 2H), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C19H20Br2N5O4P: C, 39.81; H, 3.52; N, 12.22%. Found C, 39.48; H, 3.78; N, 11.79%.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1([S:23]([NH:26][C:27](=[O:49])[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[CH:29]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[K+]>CN(C)C=O>[C:17]1([S:23]([NH:26][C:27](=[O:49])[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[CH:29]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
Triethylamine (0.115 g) and 0.200 g of benzoyl chloride were added to a solution of 0.500 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 5 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 15 hours. A potassium hydrogencarbonate aqueous solution was added thereto to stop the reaction. The solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of water and methanol, and the solution was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were collected, and were dried to obtain 0.393 g of crude N-benzenesulfonyl-4-benzoylamino-3-(biphenyl-4-ylmethyl-amino)benzamide. This crude product was converted to 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenyl-benzimidazole [(246), 0.270 g] in the same manner as in Example 183.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.N1C=CC=CC=1.[C:19](Cl)(=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29].Cl>O.C1(C)C=CC=CC=1>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:9]=[CH:10][CH:11]=[CH:12]1)(=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]
Reactant: C=CCCCCCCCCC(=O)Cl
Reactant: OCCCCCCn1cccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C=CCCCCCCCCC(=O)OCCCCCCn1cccc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
62.0 g (0.371 mol) of N-(6-hydroxyhexyl)-pyrrole, 33.2 g (0.420 mol) of dry pyridine, and 1850 ml of dry toluene were put in a 2-liter reactor, and 300 ml of a dry toluene solution of 75.7 g (0.373 mol) of 10-undecenoylchloride was dropped thereto at 20° C. or below. The dropping time was 30 minutes. Thereafter, the mixture was stirred at the same temperature for one hour. The reaction mixture was poured into 1.5 liter of iced water, and was made acidic with use of 1N hydrochloric acid. It was subjected to ethyl acetate extraction, an organic layer was washed with water and concentrated brine and was dried using anhydrous magnesium sulfate, and the solvent was removed. As a result, 128.2 g of crude substance was obtained. This was subjected to purification by silicagel column with use of n-hexane/acetone=20/1, whereby 99.6 g of N-[6-(10-undecenoyloxy)hexyl]-pyrrole was obtained. The yield was 80.1%. The reaction of the step 4 is expressed by a reaction formula (15) shown below:
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([C:23]3[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=3)[CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[K+].[C:34]([C:36]1[N:37]=[C:38]([C:49]([O-])=[O:50])[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=1)#[N:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:49]([C:38]3[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=[C:36]([C:34]#[N:35])[N:37]=3)=[O:50])=[C:18]([C:23]3[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=3)[CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC=C(c2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 62 %

Procedure:
A solution of 4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-ylmethyl}-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (as prepared in the previous step, 233 mg, 0.590 mmol) in CH2Cl2 (10 mL) was treated with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d), 188 mg, 0.610 mmol), PyBroP (332 mg, 0.713 mmol), and DIEA (177 μL, 10.2 mmol) at RT for 1 h. The mixture was diluted with CH2Cl2 (40 mL) and washed with water (1×30 mL) and satd aq NaHCO3 (1×30 mL). The combined aqueous layers were extracted with CH2Cl2 (1×30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 20-g Isolute SPE column on a FlashMaster system with 10-25% EtOAc-hexane afforded the title compound (223 mg, 62%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C38H62N6O3Si2, 707.4 (M+H). found 707.4.
Reaction SMILES: [CH3:1][C:2]([S:23]([CH3:26])(=[O:25])=[O:24])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+].O>O1CCCC1.CO.Cl>[CH3:1][C:2]([S:23]([CH3:26])(=[O:24])=[O:25])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCc1ccc(Oc2ccccc2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate (312 mg, 0.829 mmol) in tetrahyrofuran/methanol (4:1, 10 mL) was added a solution of lithium hydroxide monohydrate in water (1.66 M, 3.32 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCl (1 N in water) and extracted with ether 2×. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoic acid as an oil. 285 mg. LCMS: (M−1) 347.3
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.6 M n-Butyllithium in hexanes (9.6 mL, 15 mmol) was added dropwise to a solution of N,N-diisopropylamine (2.3 mL, 16 mmol) in THF (43 mL) at −78° C. Following complete addition, the temperature of the reaction was raised to 0° C. for 30 minutes and then was re-cooled to −78° C. 5-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (3.00 g, 10.2 mmol, from Example 2, Step 1) in THF (8 mL) was added dropwise and the reaction was stirred for 1 hour, at which time ethyl chloroformate (1.4 mL, 14 mmol, Alfa Aesar) was added. The reaction was allowed to stir at −78° C. for 2 hours and was then allowed to warm to room temperature. The mixture was poured into dilute HCl and extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted, and the solvent was removed in vacuo. Flash chromatography eluting with a gradient from 0-50% EtOAc in hexanes afforded product as an off white solid (1.8 g, 48%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=O)=[C:9]([F:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>[Cl-].[Na+].O.O1CCCC1>[CH2:23]([O:30][N:31]=[CH:11][C:10]1[C:2]([F:1])=[C:3]([CH:7]=[C:8]([F:14])[C:9]=1[F:13])[C:4]([OH:6])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c(F)c(C=NOCc2ccccc2)c1F
Yield: 100 %

Procedure:
2,4,5-Trifluoro-3-formylbenzoic acid (Horiuchi N., Yonezawa T., Chiba K., Yoshida H., PCT Int. Appl. [1999] WO 97-JP2918), (5.70 g, 27.9 mmol), triethylamine (11 mL, 78.9 mmol), O-benzylhydroxylamine hydrochloride (4.47 g, 28.0 mmol) and anhydrous tetrahydrofuran (150 mL) are stirred at room temperature for 50 hours. The mixture is poured into brine and the pH adjusted to 5.5-6.0 using 1.0 M hydrochloric acid. The mixture is extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered, and concentrated in vacuo to provide 3-(benzyloxyiminomethyl)-2,4,5-trifluorobenzoic acid (8.63 g), which is used without further purification. 1H NMR (200 MHz, CDCl3): δ 9.82-9.18 (bs, 1H), 8.24 (s, 1H), 7.94-7.68 (m, 1H), 7.55-7.23 (m, 5H), 5.23 (d, 2H). MS (EI, M−1) m/z 308.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][CH2:30][C:31]([NH:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([N:40]([CH:48]([CH3:50])[CH3:49])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36][C@H:35]1[CH2:51][OH:52])=[O:32]>C1COCC1.O>[OH:52][CH2:51][C@H:35]1[C@@H:34]([NH:33][C:31](=[O:32])[CH2:30][NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)[CH2:39][CH2:38][C@@H:37]([N:40]([CH:48]([CH3:50])[CH3:49])[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[CH2:36]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CN)[C@H](CO)C1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
A solution of 3-Trifluoromethyl-benzoic acid (0.55 g, 0.0029 mol) in THF was cooled in an ice bath and treated with N-methylmorpholine (0.3 g, 0.003 mol) and then drop-wise with isobutyl chloroformate (0.39 g, 0.0029 mol). The resulting mixture was stirred for 5 min and then treated with a solution of tert-butyl(1R,3R,4S)-4-(2-aminoacetamido)-3-(hydroxymethyl)cyclohexyl-(isopropyl)carbamate (2.8 g, 0.01 mol) in THF. The resulting mixture was stirred for 30 minutes and then diluted with water and extracted into CH2Cl2. The extract was washed with dilute NaOH, water, and brine and then concentrated under vacuum. The residue was chromatographed on silica gel (elution 55% ethyl acetate/hexane, then 100% ethyl acetate) to give 1.4 g of tert-butyl(1R,3R,4S)-3-(hydroxymethyl)-4-(2-(3-(trifluoromethyl)-benzamido)acetamido)cyclohexyl(isopropyl)carbamate as a white solid. MS found: (M+H)+=516.3.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.Cl[CH2:7][N:8]([CH3:13])[S:9]([Cl:12])(=[O:11])=[O:10]>C1C=CC=CC=1>[CH3:1][O:2][CH2:7][N:8]([CH3:13])[S:9]([Cl:12])(=[O:11])=[O:10]
Reactant: CN(CCl)S(=O)(=O)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COCN(C)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 13.5 parts of sodium methylate in 110 parts of methanol is added, in the course of 15 minutes at from 0° to 5° C., to a mixture of 44.5 parts of N-chloromethyl-N-methylsulfamic acid chloride in 260 parts of benzene. The reaction mixture is then stirred for 2 hours at 25° C., after which the sodium chloride which has precipitated is filtered off. After removing the solvent under reduced pressure, distillation gives 29.1 parts (67% of theory) of N-methoxymethyl-N-methylsulfamic acid chloride of boiling point 84°-87° C./12 mbar and nD25 =1.4536.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[NH2:13][OH:14].Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[N:13][OH:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: NO
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=NO)cc1OC
Reaction time: 1 h
Yield: 7154.4 %

Procedure:
After dissolving 3,4-dimethoxybenzaldehyde (1.00 g, 0.081 mmol) in 60 mL of ethyl alcohol/water (1/1, v/v) solution, H2NOH HCl (0.54 g, 7.823 mmol) was added. While stirring the reaction mixture, Na2CO3 (0.83 g, 7.823 mmol) was added slowly at below 0° C. The reaction was continued for 1 hr in an oil bath preheated to 60-65° C. After the reaction was completed, 1.05 g (96.4%) of the target product was obtained by extracting with ethyl acetate, drying over anhydrous MgSO4 and removing the solvent under reduced pressure.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([C:21]3[C:22]4[CH:49]=[C:48]([Cl:50])[CH:47]=[CH:46][C:23]=4[N:24]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)[C:25](=[O:36])[C@H:26]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])[N:27]=3)[CH:19]=[CH:20][C:15]=2[NH:14][C:13]1=[O:51])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:50][C:48]1[CH:47]=[CH:46][C:23]2[N:24]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[C:25](=[O:36])[C@H:26]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:27]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]4[NH:14][C:13](=[O:51])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:16]=4[CH:17]=3)[C:22]=2[CH:49]=1
Reactant: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c4c3)c3cc(Cl)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(CCCO)c4c3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-5-(3-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (100 mg, 0.134 mmol) was dissolved in DCM (˜10 mL) and treated with 0.5 mL trifluoroacetic acid. After 1.5 hr, the reaction was ˜30% complete by TLC. Another 0.5 mL trifluoroacetic acid was added. After another 1.5 hr, another 0.5 mL trifluoroacetic acid was added. This mixture was allowed to stir at room temperature overnight. It was still mostly starting material by TLC. The solvent was evaporated and azeotroped 3× from DCM. 4 M HCl in 1,4-dioxane (3 mL) was added. This mixture was stirred at RT under nitrogen for 1 hr. TLC (quenched in Et3N-DCM) showed all starting material had converted. The solvent was evaporated to give the title compound as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[C:9]1[C:18](C)=[C:17]2[C:12]([C:13](=[O:32])[CH2:14][C:15]([CH3:31])([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[O:16]2)=[CH:11]C=1.N1C=CC=CC=1.C1C=CC=CC=1>O>[C:5]([O:4][C:1]1[C:18]([CH3:9])=[C:17]2[C:12]([C:13](=[O:32])[CH2:14][C:15]([CH3:31])([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[O:16]2)=[CH:11][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)ccc2c1OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)Oc1ccc2c(c1C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Reaction time: 8 h
Yield: 92.9 %

Procedure:
3.3 g of acetic anhydride were added to a mixture of 9.3 g of 7-hydroxy-2,8-dimethyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 16), 50 ml of pyridine and 50 ml of benzene and allowed to stand overnight. The reaction mixture was then poured into water and extracted with benzene. The benzene extract was washed with 5% w/v aqueous hydrochloric acid and then with water, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 20:1 by volume mixture of benzene and ethyl acetate, to obtain 9.7 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH:6]([CH:8]=[CH2:9])=[O:7]>>[CH3:5][C:3]1[CH2:4][CH2:9][CH:8]([CH2:6][OH:7])[CH2:1][CH:2]=1
Reactant: C=CC(=C)C
Reactant: C=CC=O
Product: CC1=CCC(CO)CC1

Procedure:
According to the well known Diels-Alder Reaction, using isoprene and acrolein as raw materials, 4-methyl-3-cyclohexenyl aldehyde was synthesized. The reaction was conducted under the conditions described in the literary documents of J. Amer, Chem. Soc., 119, 15, 1997, 3507–3512; and Tetrahedron Lett., 40, 32, 1999, 5817–5822. Subsequently, the compound was reduced to obtain 4-methyl-3-cyclohexenylmethanol at a high yield.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:11][C@@H:9]2[CH2:10][C@H:8]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and 4-fluorobenzaldehyde (0.18 mL, 1.65 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.41 g, 1.95 mmol) was slowly added and stirring continued for 1.5 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (3% MeOH/CH2Cl2) affording 0.18 g of N-(4-fluorobenzyl)-N-[(trans)-2-phenylcyclopropyl]amine [Rf=0.5 (5% MeOH/CH2Cl2), colorless oil, 49% yield].