Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[C:17]1\[CH2:18][O:19][CH2:20][CH2:21][CH2:22]\1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[B-](F)(F)(F)F.C[C@H]1CC[C@H](C)P1CCP1[C@@H](C)CC[C@@H]1C.C1CC=CCCC=C1.[Rh]>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C(NC(=O)OCc1ccccc1)=C1\CCCOC1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C@H]1CC[C@H](C)P1CCP1[C@@H](C)CC[C@@H]1C
Solvent: C1=CCCC=CCC1
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H]1CCCOC1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
(−)-1,2-Bis((2S,5S)-2,5-dimethylphospholano)ethane(cyclooctadiene)-rhodium(I)tetrafluoroborate (28.2 mg, 0.051 mmol) was added to a stirred solution of (Z)-methyl 2-(benzyloxycarbonylamino)-2-(2H-pyran-3(4H,5H,6H)-ylidene)acetate (310 mg, 1.015 mmol) in MeOH (10 mL) and the mixture was vacuum flushed with N2, followed by Hz, and then the reaction was stirred under H2 (60 psi) at rt for 2d. The reaction mixture was concentrated and the residue was purified by flash silica chromatography (loading solvent: DCM, eluted with 20% EtOAc in hexanes) to yield (S)-methyl 2-(benzyloxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (204 mg) as clear colorless oil. LC-MS retention time 1.437 min; m/z 307.89 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 7.30-7.46 (m, 5H), 5.32 (d, J=8.8 Hz, 1H), 5.12 (s, 2H), 4.36 (dd, J=8.9, 5.6 Hz, 1H), 3.84-3.98 (m, 2H), 3.77 (s, 3H), 3.28-3.37 (m, 1H), 3.23 (dd, J=11.3, 10.5 Hz, 1H), 2.04-2.16 (m, 1H), 1.61-1.75 (m, 3H), 1.31-1.43 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:33])[CH2:19][CH2:18]2)=[O:16])[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][CH:10]([NH:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([N:23]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]2=[O:33])[CH2:21][CH2:22]1)=[O:16])[C:11]([N:44]1[CH2:45][CH2:46][CH:41]([CH:38]2[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]2)[CH2:42][CH2:43]1)=[O:13]
Reactant: CN1CCC(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Product: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 83d) from 3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 1-methyl-[4,4′]bipiperidinyl.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH2:19][CH2:20][F:21])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:22])([CH2:18][CH2:19][CH2:20][F:21])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]CCCC
Reactant: N#CC(CCCF)N=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)(CCCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 107.8 %

Procedure:
16.73 g (59.68 mmol) of rac-2-[(diphenylmethylene)amino]-5-fluoropentanonitrile from Example 68A were initially charged in 394 ml of abs. THF, and 24.11 ml (60.27 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 34.93 g (238.70 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 4.5 h. The reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 18.94 g of the target compound were obtained (95% of theory, 88% purity).
Reaction SMILES: [CH3:1][CH:2]1[CH2:33][O:32][C:5]2([O:9][CH:8]3[CH2:10][CH:11]4[CH:16]5[CH2:17][CH:18]=[C:19]6[CH2:24][CH:23]([O:25][C:26]([CH3:28])=[O:27])[CH2:22][CH2:21][C:20]6([CH3:29])[CH:15]5[CH2:14][CH2:13][C:12]4([CH3:30])[CH:7]3[CH:6]2[CH3:31])[CH2:4][CH2:3]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>Cl.N1C=CC=CC=1>[CH3:31][C:6]1[C@@H:7]2[C@:12]3([CH3:30])[C@@H:11]([CH2:10][C@@H:8]2[O:9][C:5]=1[CH2:4][CH2:3][C@H:2]([CH2:33][O:32][C:34]([CH3:35])=[O:36])[CH3:1])[C@@H:16]1[CH2:17][CH:18]=[C:19]2[CH2:24][C@@H:23]([O:25][C:26]([CH3:28])=[O:27])[CH2:22][CH2:21][C@:20]2([CH3:29])[C@H:15]1[CH2:14][CH2:13]3
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OC1CCC2(C)C(=CCC3C2CCC2(C)C3CC3OC4(CCC(C)CO4)C(C)C32)C1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](C)CCC1=C(C)[C@H]2[C@H](C[C@H]3[C@@H]4CC=C5C[C@@H](OC(C)=O)CC[C@]5(C)[C@H]4CC[C@@]32C)O1
Yield: 84 %

Procedure:
Another group of workers, Dauben et al have reported a process in which diosgenin acetate is heated in acetic anhydride containing pyridine hydrochloride as catalyst which afforded pseudodiosgenin diacetate in 84% yield. (Ref:Dauben WG and Fonken GJ; J Am Chem Soc, 76, 4618, 1954).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])=[CH:6][C:5]=1[N:24]=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][C:27]=1[N+:38]([O-])=O>O>[C:32]1([C:29]2[CH:30]=[CH:31][C:26]3=[N:25][N:24]([C:5]4[CH:6]=[C:7]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:8]=[C:9]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:4]=4[OH:3])[N:38]=[C:27]3[CH:28]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(-c4ccccc4)cc3n2)c1

Procedure:
To a solution of sodium hydroxide (6 g, 0.15 mol) in 8 mL of water is added 2-hydroxy-2′nitro-3,4′-diphenyl-5-tert-octylazobenzene (6.56 g), prepared in (D) above. The reaction mixture is heated to reflux and then formadine sulfinic acid (10.8 g, 0.1 mol) is added portionwise over 20 minutes. The reaction mixture is heated at reflux for 1.5 hours. To the cooled reaction mixture is added 200 mL of water and the ethanol is removed under vacuum. The reaction mixture is adjusted to pH 4 with hydrochloric acid. The resultant mixture is extracted twice with methylene chloride and the combined organic phases are extracted with water. The organic phase is dried over anhydrous magnesium sulfate, and the solvent is then removed under vacuum. The residue is recrystallized sequentially from a mixture of water and methanol, and petroleum ether to give the title compound as a white solid melting at 123-125° C.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[CH:26][CH:27]=2)\[CH3:21])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(OC)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(OC)c3)cc2)cc1)C(=O)O
Yield: 83.6 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate (example 113) (230 mg, 0.49 mmol) and sodium hydroxide (1M, 0.97 ml, 0.97 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-2-ethoxy-3-{4-[3-(3′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}propionic acid (183 mg, 85%) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[C:7]#[N:8].[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:7]([C:6]1[S:5][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][C:2]=1[NH:1][C:15](=[O:17])[CH3:16])#[N:8]
Reactant: CC(=O)Cl
Reactant: N#Cc1sc(N2CCOCC2)nc1N
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(N2CCOCC2)sc1C#N
Temperature: 80 °C
Yield: 81.8 %

Procedure:
To a 5 L round bottom flask equipped with a mechanical stirrer was added 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-carbonitrile (200 g, 951 mmol) and N,N-dimethylaminopyridine (23.24 g, 190 mmol). The solids were taken up in Pyridine (2000 mL) and to this reaction solution was added acetyl chloride (74.7 g, 951 mmol) via an addition funnel. The reaction was heated to 80° C. and monitored by LCMS for conversion to product. Upon complete conversion (˜2 hours), the reaction was cooled to room temperature and the reaction was concentrated to a slurry, then subsequently diluted with a mixture of 0.1N NaOH (2 L) solution and methanol (140 mL). The mixture was rapidly stirred using a mechanical stirrer for 15 min, then the resulting precipitate was collected by filtration to provide the desired N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (218.2 g, 778 mmol, 82% yield) as a brown solid (1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H) 3.40-3.53 (m, 4H) 3.62-3.77 (m, 4H) 10.88 (s, 1H)).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:42][O-].[Na+]>C(Cl)Cl.CO>[CH3:42][O:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:35])([F:36])[F:34])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: C[O-]
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COCc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with sodium methanolate (5.4M, 1 ml) in MeOH (5 ml)/CH2Cl2 (5 ml) according to the general procedure of Example 288. Obtained as an off-white solid (94 mg, 36%).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1.Cl[C:14]1[C:23]2[C:18](=[C:19]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:32])[CH:15]=1.OP([O-])(O)=O.[K+]>CS(C)=O>[CH:27]1([O:26][C:19]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[C:23]3[C:18]=2[O:17][C:16](=[O:32])[CH:15]=[C:14]3[NH:3][C@@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(N[C@H]3CC[C@@H](C(=O)O)CC3)cc(=O)oc2c1OC1CCCC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (50 mg, 60%, 1.25 mmol) was added to a solution of cis-4-amino-1-cyclohexanecarboxylic acid (83 mg, 0.580 mmol) and anhydrous DMSO (2 mL) at rt under N2. After 10 min, 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (114 mg, 0.387 mmol, Example 7, Step 1) was added, and the mixture was stirred for 3 d, poured into 1M KH2PO4 and extracted with ethyl acetate. The extract was dried, filtered, concentrated, and purified by reverse-phase HPLC (30→100% MeCN/H2O) to give cis-4-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)cyclohexanecarboxylic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.85 (d, 1H), 7.10 (d, 1H), 7.01 (d, 1H), 5.10 (s, 1H), 4.81 (m, 1H), 3.87 (s, 3H), 3.50 (m, 1H), 2.56 (m, 1H), 2.04 (m, 2H), 1.79-1.58 (m, 14H); MS (ESI): 402.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([O:52]C)=[O:51])[CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-].C1COCC1.O.Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([OH:52])=[O:51])[CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)OC)c3ccccc3n2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
2-[1-(4-(Ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-(methoxycarbonyl)-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (170 mg, 0.229 mmol) was treated with LiOH (2.0 eq.) in a solution of THF:H2O (3:1, 12 mL). The reaction mixture was stirred at ambient temperature for 5 hours. The pH value of the reaction mixture was adjusted to between pH 3 and pH4 with 1N HCl solution. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with H2O and brine. The solvent was evaporated to give 2-[l-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-carboxy-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (150 mg); NMR (CD3OD) 1.30 (t, 3), 1.40 (s, 9), 1.50 (s, 9), 1.90 (m, 1), 2.15 (m, 2), 2.30–2.50 (m, 5), 3.45–3.90 (m, 8), 4.18 (q, 2), 4.75 (m, 1), 5.25 (m, 1), 7.75 (m, 1), 7.90 (m, 1), 8.25 (m, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:21]2[CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C:17](=[O:26])[NH:16][C:15]=2[CH:14]=[CH:13][C:12]=1[O:27][CH3:28]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:21]3[CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C:17](=[O:26])[NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[O:27][CH3:28])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: COc1ccc2c(c1N)CN(S(C)(=O)=O)CC(=O)N2
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: COc1ccc2c(c1Nc1nc(Cl)ncc1Cl)CN(S(C)(=O)=O)CC(=O)N2
Temperature: 120 °C

Procedure:
A mixture of 2,4,5-Trichloro-pyrimidine (1.5 g, 0.0084 mol), 6-Amino-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.400 g, 0.00140 mol) was heated at 120° C. for 48 hrs. The reaction was triturated with ethyl acetate and then with methanol giving 6-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one the product as a gray solid (0.338 g, 51%). Mp 280-300d; LCMS (m/e) 432 (M); 1H-NMR (DMSO, 400 MHz) δ 10.23 (s, 1H), 9.34 (s, 1H), 8.34 (s, 1H), 7.20-7.17 (d, 1H, J=9.10 Hz), 7.14-7.11 (d, 1H, J=8.84 Hz),4.40-4.30 (m, 1H), 4.25-4.10 (m, 1H), 3.83 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[C:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])=[N-]>CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[C:1]1([C:7]2[C:17]([C:22]([O:24][CH3:25])=[O:23])([C:18]([O:20][CH3:21])=[O:19])[C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Product: COC(=O)C1(C(=O)OC)C(c2ccccc2)=C1c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A 100 millilater round-bottom flask was equipped with a magnetic stirrer and reflux condenser with N2 inlet. The flask was charged with 25.0 grams (0.140 mole) of diphenylacetylene and 140 milligrams of cupric acetylacetonate. The mixture was heated to 120° C. using an oil bath and 8.85 grams (0.056 mole) of dimethyl diazomalonate was added over 24 hours using a syringe pump. When all of the dimethyl diazomalonate had been added, heating at 120° C. was continued for 8 hours. The diphenylacetylene was distilled off under vacuum, boiling point 170° C./19 Mm. The residue was purified by flash chromatography eluting with 75:25 hexane-ethyl acetate to give 4.65 grams (0.015 mole) of the desired product as a white solid. NMR analysis of the product indicated the following:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([F:44])[C:42]=1F)[C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:38]([C:37]1[CH:36]=[C:35]([F:34])[C:42]([N:11]2[CH2:12][CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[C:41]([F:44])[CH:40]=1)#[N:39]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C#N)cc2F)CCC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of 200 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 212 mg of 3,4,5-trifluorobenzonitrile, and 187 mg of potassium carbonate in 4.0 mL of DMSO was heated at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 191 mg of tert-butyl {[1-(4-cyano-2,6-difluorophenyl)-4-phenylpiperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless foamy substance. ESI+: 582
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-:39][Si](C)(C)C)(C)C.[Na+].C1(P(C2C=CC=CC=2)(ON)=O)C=CC=CC=1>CN(C=O)C.C1COCC1>[NH2:39][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:11])[CH:7]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:6]2[N:5]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[C:4]1=[O:34]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccncc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3ccncc3)C3C=CC=CC32)C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 80 mg (0.175 mmol) 2-(2,4-Dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl )-acetamide in 3 mL DMF was added 0.210 mL (0.209 mmol, 1.2 equiv) 1N Sodium bis(trimethylsilyl)amide in THF at 0° C. After stirring 0.5 h, 62 mg (0.262 mmol; 1.5 equiv) O-(diphenyl-phosphinyl)hydroxylamine (Harger, J. C. S. Perkin I, 3284-3288 (1981)) was added and the reaction mixture stirred 16 h at ambient temperature. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product was purified by flash chromatography on 5 g silica gel eluted successively with EtOAc (100 mL), DCM/CH3OH (19:1, 100 mL). Appropriate fractions were combined and concentrated in vacuo to give the title compound as a clear glass: low resolution MS (FAB) m/z 474.2 (MH+); TLC Rf=0.31 (DCM/CH3OH, 19:1)).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([S:26]([N:29]([CH3:34])[CH2:30][C:31]([OH:33])=[O:32])(=[O:28])=[O:27])=[CH:23][CH:24]=2)[C:19]([NH:35][C:36]([NH2:38])=[NH:37])=[N:18][CH:17]=1.[H-].[Na+].[C:41](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)C)([CH3:44])([CH3:43])[CH3:42]>COCCOC>[C:41]([O:32][C:31](=[O:33])[CH2:30][N:29]([S:26]([C:22]1[CH:21]=[C:20]2[C:25]([C:16]([Cl:15])=[CH:17][N:18]=[C:19]2[NH:35][C:36]([NH2:38])=[NH:37])=[CH:24][CH:23]=1)(=[O:27])=[O:28])[CH3:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 50 °C

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-methylglycine bis(trifluoroacetate) ##STR15## Guanidine hydrochloride (286 mg, 2.99 mmol was added in one portion to a stirred suspension of NaH (77.5 mg, 80% dispersion by wt in mineral oil, 2.58 mmol) in DME (2.0 mL) and the mixture was heated at 50° C. under N2 for 20 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-methylglycine t-butyl ester (393 mg, 0.97 mmol) in DME (10 mL) was added and the mixture heated at 90° C. for 2 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-methylglycine t-butyl ester (260 mg, 0.607 mmol) as an off-white foam
Reaction SMILES: [CH3:1][C@:2]12[C:10](=[O:11])[CH2:9][C@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3]2.C[C@@]12C(=O)C[C@@H](C1(C)C)CC2.[N:23](OCCC(C)C)=O.[Na].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:23][CH:9]1[CH:5]2[C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH2:3][CH2:4]2)[CH:10]1[OH:11]
Reactant: CC(C)CCON=O
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Agent: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2
Agent: [Al+3]
Agent: [H-]
Product: CC1(C)C2CCC1(C)C(O)C2N

Procedure:
These compounds can be synthesized as follows. D-camphor or L-camphor is reacted with isoamyl nitrite in the presence of metallic sodium, and the product is reduced with lithium aluminum hydride to obtain 3-amino-2-hydroxybornane. The resulting 3-amino-2-hydroxybornane is reacted with furoyl chloride, 2-thiophenecarbonyl chloride-, or benzoyl chloride in the presence of pyridine or 4-dimethylaminopyridine, or it is subjected to a dehydrating reaction with furfural, 1-methyl-2-pyrrolecarbaldehyde, 1-benzyloxycarbonyl-L-proline, or benzaldehyde in the presence of a dehydrating agent. The resulting product is then reduced with lithium aluminum hydride to obtain a 3-amino-2-hydroxybornane derivative of exo or endo form.