Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=[C:30]=[O:31])=[CH:26][CH:25]=1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:30]([NH:29][CH2:28][C:27]4[CH:32]=[CH:33][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[O:31])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: COc1ccc(CNC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1

Procedure:
The title compound, MS: m/e=439.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-methoxybenzyl isocyanate.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 5.5 g (29 mmol) 5-trimethylsilanylethynyl-pyridin-2-ylamine (A5) and 2.0 g (14 mmol) K2CO3 in 30 mL MeOH. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 2.9 g (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.[CH3:31][NH:32][CH2:33][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1>O1CCCC1.C(OCC)C.C(Cl)Cl>[CH3:31][N:32]([CH2:33][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[C:15](=[O:17])[C:14]#[C:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C#CC(=O)O)cc(OC)c1OC
Reactant: CNCC=Cc1ccc(OC)c(OC)c1
Agent: CCOC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C=CCN(C)C(=O)C#Cc2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
To the solution of 11.6 g of 3,4,5-trimethoxyphenylpropiolic acid in 60 ml of tetrahydrofuran, 6.0 g of triethylamine are added while stirring, followed by 60 ml of diethyl ether. The mixture is cooled with ice and to the resulting suspension the solution of 5.35 g of ethyl chloroformate in 30 ml of diethyl ether is added dropwise. The mixture is stirred for 15 minutes at 0°-5°, whereupon the solution of 9.7 g of N-methyl-3,4-dimethoxycinnamylamine in 30 ml of diethyl ether is added dropwise, followed by 50 ml of methylene chloride. The mixture is stirred for 30 minutes at room temperature and washed with N hydrochloric acid, 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated under reduced pressure, to yield the N-methyl-N-(3,4-dimethoxycinnamyl)-3,4,5-trimethoxyphenylpropiolamide.
Reaction SMILES: BrC1C2C(=CC=C(F)C=2)C(=O)N(C)C=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.FC1C=C2C(=CC=1)C(=O)N(C)C=C2B1OC(C)(C)C(C)(C)O1.ClC1C(OCC2CC2)=CN=C(S(C)(=O)=O)N=1.[CH:71]1([CH2:74][O:75][C:76]2[C:77]([C:86]3[C:95]4[C:90](=[CH:91][CH:92]=[C:93]([F:96])[CH:94]=4)[C:89](=[O:97])[N:88]([CH3:98])[CH:87]=3)=[N:78][C:79](S(C)(=O)=O)=[N:80][CH:81]=2)[CH2:73][CH2:72]1.[CH3:99][S:100]([NH2:103])(=[O:102])=[O:101]>>[CH:71]1([CH2:74][O:75][C:76]2[C:77]([C:86]3[C:95]4[C:90](=[CH:91][CH:92]=[C:93]([F:96])[CH:94]=4)[C:89](=[O:97])[N:88]([CH3:98])[CH:87]=3)=[N:78][C:79]([NH:103][S:100]([CH3:99])(=[O:102])=[O:101])=[N:80][CH:81]=2)[CH2:72][CH2:73]1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2cc(F)ccc2c1=O
Reactant: CS(N)(=O)=O
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cc(F)ccc2c1=O
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)c2cc(F)ccc2c1=O

Procedure:
The title compound of Example 47, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-fluoro-2-methylisoquinolin-1-one was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.14 (brs, 1H), 8.56 (s, 1H), 7.96 (dd, J1=9.2 Hz, J2=3.2 Hz, 1H), 7.88 (s, 1H), 7.85 (dd, J1=9.2 Hz, J2=3.6 Hz, 1H), 7.62-7.55 (m, 1H), 3.94 (d, J=6.8 Hz, 2H), 3.60 (s, 3H), 3.32 (s, 3H), 1.11-0.99 (m, 1H), 0.47-0.40 (m, 2H), 0.23-0.16 (m, 2H). LCMS: 419.0 (M+1)+
Reaction SMILES: Cl.COC1C=C(C=C(OC)C=1OC)C([NH:9][CH2:10][CH:11]([OH:25])[CH2:12][N:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.COC1C=C(C=C(OC)C=1OC)C(Cl)=O>>[NH2:9][CH2:10][CH:11]([OH:25])[CH2:12][N:13]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cc(C(=O)NCC(O)CN(Cc2ccccc2)C(C)(C)C)cc(OC)c1OC
Agent: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Product: CC(C)(C)N(Cc1ccccc1)CC(O)CN
Yield: 78 %

Procedure:
1-(3,4,5-trimethoxy benzamido)-3-(N-benzyl tert-butylamino)-2-propanol hydrochloride, starting from 7.8 g (0.034 mole) of 3,4,5-trimethoxy benzoyl chloride and 8 g (0.034 mole) of 1-amino-3-(N-benzyl tert-butylamino)-2-propanol (yield 78 %).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6](Cl)[N:7]=1.[F:10][C:11]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:11]=2[F:10])[N:7]=1
Reactant: Clc1nnc(Cl)c(Cl)n1
Reactant: NCc1cccc(F)c1F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Fc1cccc(CNc2nc(Cl)nnc2Cl)c1F
Temperature: 25 °C

Procedure:
3,5,6-Trichloro-1,2,4-triazine (520 mg, 2.8 mmol) was dissolved in 5 mL NMP. To it was added 2,3-difluorobenzylamine (0.36 mL, 3.1 mmol) and DIEA (0.54 mL, 3.1 mmol). The mixture was stirred at RT for 20 m. It was diluted with EtOAc, washed with brine twice, dried over MgSO4, concentrated in vacuo, and subjected to flash column to afford 3,6-dichloro-N-(2,3-difluorobenzyl)-1,2,4-triazin-5-amine.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl[CH2:15][CH:16]([OH:25])[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>C(O)C.O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:15][CH:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc2c(c1)OCCO2
Yield: 33.7 %

Procedure:
A solution of benzo-1,4-dioxan-6-ol (0.15 g; Tetrahedron, 1995, 3197) in ethanol (20 ml) at room temperature was treated with a solution of sodium hydroxide (0.044 g) in water (5 ml) and was then heated at reflux. A solution of (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g) in ethanol (5 ml) was added dropwise to the latter and the resulting mixture heated at reflux for 1 hour. The reaction mixture was cooled and then water was added. The organic component was extracted with dichloromethane, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give an oil (0.100 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][NH2:12].O>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: CN
Reactant: N#Cc1c(F)cccc1F
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cccc(F)c1C#N

Procedure:
2,6-Difluorobenzonitrile, 2.78 g (20 mmol) and 5 ml (60 mmol) of 40% aqueous methylamine in 50 ml DMF is stirred at room temperature for 1 hr., poured into water and the product is collected, 2.4 g m.p. 130°-132° C.
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC=CC=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([NH:23][C:8](=[O:9])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)CC1CCCCC1
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=C(CC1CCCCC1)NC1CCCCC1

Procedure:
The N-cyclohexylcyclohexaneacetamide is prepared from cyclohexylacetyl chloride (from 10 gm. of cyclohexylacetic acid and 50 ml. of thionyl chloride, 45 minutes at reflux) in 50 ml. of dry benzene added to 14 gm. of cyclohexylamine in 100 ml. of benzene over ten minutes. The reaction is stirred at reflux for one hour, cooled and diluted with methylene chloride. The organic layer is washed with dilute hydrochloric acid, then water and sodium bicarbonate solution, dried and concentrated. Product is recrystallized from alcohol water: 11.8 gm. (76%), m.p. 164°-165°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[Cl:28][CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>ClCCl>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1)(=[O:34])=[O:33]
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOc1ccc(NS(=O)(=O)CCCCl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
368 mg (1.0 mmol) of the compound from example 44A are reacted with 266 mg (1.5 mmol) of 3-chloropropanesulfonyl chloride and 0.81 ml (10.0 mmol) of pyridine in 12 ml of dichloromethane for 3 hours.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:13]([NH2:16])=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1N=C[N:26]([C:29](N2C=NC=C2)=[S:30])C=1.[NH4+].[OH-].O>C1COCC1>[CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[C:12]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:13]([NH:16][C:29]([NH2:26])=[S:30])=[N:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1NC(N)=S
Reaction time: 72 h
Yield: 75 %

Procedure:
5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-ylamine (0.37 mmol) is dissolved in THF (5.5 ml) and 1,1-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 3 days. 32% NH4OH (20 eq.) is added and stirred 4 hours at room temperature. Water (150 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)pyridine-2-yl]-thiourea is obtained as brown oil in a yield of 75%. HPLC (method C): 1.60 min; LC-MS (method A): 1.37 min, 398.15 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (as the TFA salt) (1.0 g, 2.08 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.87 mL, 6.25 mmol). Methanesulfonyl chloride (0.24 mL, 3.12 mmol) was added slowly and stirred at rt for 30 min. At this time the reaction mixture was diluted with dichloromethane and washed with a saturated bicarbonate solution, water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure to afford 1-[3-(methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)hexahydro-1H-1,4-diazepine. (0.737 g, 2.24 mmol) as a yellow/brown solid. ESIMS (M+H)+=330.
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][CH:8]([NH:21][C:22](=[O:48])[C@H:23]([CH3:47])[NH:24][C:25](=[O:46])[C@H:26]([CH:43]([CH3:45])[CH3:44])[NH:27][C:28](=[O:42])[C@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[NH:30][C:31](=[O:33])[CH3:32])[C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)(C)C.CC(C)=O.CCCCCC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:31]([NH:30][C@H:29]([C:28]([NH:27][C@H:26]([C:25]([NH:24][C@H:23]([C:22]([NH:21][CH:8]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:7][C:6]([OH:49])=[O:5])=[O:48])[CH3:47])=[O:46])[CH:43]([CH3:45])[CH3:44])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CCCCc1ccccc1)C(C)C
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)O)C(=O)CCCCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-8-phenyl octanoic acid t-butyl ester (100 mg) was dissolved in a 1:1 mixture of CH2Cl2 /TFA (10 mL). The mixture was stirred at rt for 30 min and the solvent was reduced in vacuo. The residue was recrystilized from acetone/hexane to provide the acid (80 mg, 80%)
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:16]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)N(C)C(=O)CS2
Reactant: Cc1ccnc(N)c1
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)N(C)C(=O)CS4)nc2c1
Yield: 58.8 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-4-methyl-3-oxo-3,4-dihyro-2H-1,4-benzothiazine (1.9 g) was prepared in the substantially same manner as that of Example 4 from 6-(2-bromopropionyl)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (3.14 g) and 2-amino-4-methyl-pyridine (3.24 g).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH:23]1(C=O)[CH2:25][CH2:24]1.C([O-])=O.[NH4+]>C(O)(C)C>[CH2:23]1[CH:25]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][C@H:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:24]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: O=CC1CC1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
A round bottom flask was charged with noroxymorphone (2.19 g, 0.008 moles), isopropanol (20 mL), and cyclopropanecarboxaldehyde (1.07 g, 0.02 moles, 0.91 mL). Ammonium formate (2.40 g, 0.038 moles) was added. To this solution was added RuCl3 (anhydrous)(10 mg, 0.05 mmole). The reaction mixture was stirred at room temperature for 24 h. HPLC analysis indicated the reaction was complete. To the reaction mixture was added distilled water (1.0 mL) and the mixture was stirred for 16 h at room temperature. Then, the reaction mixture was transferred to a round bottom flask and evaporated under reduced pressure leaving a semi solid. To the semi solid was added distilled water (10 mL). To this solution was added 29% NH3/H2O (˜5 mL) adjusting the pH from 7.0 to 9.4. A white precipitate formed. The precipitate was filtered, washed with distilled water (10 mL), and dried for 16 h at 95° C. yielding (−)-naltrexone (2.35 g, 0.007 moles, 91% yield) as an off white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:7][CH:8]=1.[OH-].[Na+]>>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1-c1ccc(N(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1ccc(-c2ccccc2C(=O)O)nc1
Yield: 90.5 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 3-dimethylaminopyridine-6-ylbenzoate (277 mg), which is the product of Reference example 34(a), and aqueous sodium hydroxide solution (1N, 2.20 ml) and the reaction mixture was treated to afford the title compound (237 mg)as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[F:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])[O:13][C:14]=2[CH:20]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2ccc(F)cc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2ccc(F)cc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-6-fluorobenzoxazole (71 mg, 0.25 mmol) and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the title compound was obtained (84 mg, 73%). 1H NMR (DMSO) δ 8.41(dd, 1H), 8.36(t, 1H), 8.30(s, 1H), 8.07(m, 2H), 7.84(m, 1H), 7.77(dd, 1H), 7.46(dd, 1H), 7.29(m, 1H), 7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS 458.1 m/z (M−H)−.
Reaction SMILES: [OH:1][C@@H:2]([C@H:8]([OH:25])[C:9](=[O:24])[NH:10][C@H:11]([C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:26](Cl)(Cl)=[O:27]>C(Cl)(Cl)(Cl)Cl>[CH3:14][CH:13]([CH3:15])[CH2:12][C@H:11]([NH:10][C:9]([C@H:8]1[O:25][S:26](=[O:27])[O:1][C@@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:24])[C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)[C@H]1OS(=O)O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C

Procedure:
Ethyl (2S,3S)-2,3-dihydroxy-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]propionate (305 mg) obtained in Example 2 was dissolved in carbon tetrachloride (6 ml). Thionyl chloride (69 μl) was added to the resultant solution at room temperature, and the solution was heated under reflux for 40 minutes. The reaction solution was condensed under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (a developing solvent; hexane:ethyl acetate=2:1) to obtain 174 mg of a target compound as white crystals. This product was a diastereomer mixture due to 2-position asymmetry. Therefore, the mixture was subjected to silica gel column chromatography again to obtain a high-polarity isomer (compound A) and a low-polarity isomer (compound B). NMR data and SIMS data of the compounds A and B were as follows.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(C1(C2C=CC(OC)=C(C=2)[CH:26]=[O:27])CC1)#N>>[C:12]([C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH:7]=1)[CH:26]=[O:27])([CH3:15])[CH3:14])#[N:13]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: CC(C)Oc1ccc(C(C)(C)C#N)cc1
Product: CC(C)Oc1ccc(C(C)(C)C#N)cc1C=O

Procedure:
This compound was prepared from Compound 40 in the same manner of Compound 2.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:28]([NH:62][CH:59]5[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]5)=[O:29])=[N:26][CH:27]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)nc3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cn2)CC1

Procedure:
The title compound was synthesized from 5-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)picolinic acid as described in the general procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.04 (m, 13 H) 2.77 (d, J=5 Hz, 2 H) 3.01-3.22 (m, 2 H) 3.34 (s, 3 H) 3.47 (d, J=11 Hz, 2 H) 4.08 (m, 3 H) 4.80 (m, 1 H) 7.85-8.02 (m, 1 H) 8.30 (s, 1 H) 8.44 (dd, J=9, 2 Hz, 1 H) 8.69 (d, J=8 Hz, 1 H) 8.80-8.92 (m, 1 H) 9.85-10.01 (m, 1 H). [M+H] calc'd for C25H32F2N8O2, 516; found 516.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][C:8]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=1)[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C.[Sn](Cl)(Cl)(Cl)Cl>ClCCl.C(O)C>[NH2:13][C:12]1[C:8]([CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[N:9][N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: CCOC(=O)CNCc1nn(Cc2ccccc2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1nn(Cc2ccccc2)cc1N)C(=O)c1ccc(Cl)cc1

Procedure:
1.5 g (4.7 mol) of ethyl[((1-benzyl-4-nitro-1H-pyrazol-3-yl)methyl)amino]acetate was dissolved in 50 ml of dichloromethane: 0.71 ml (5.6 mmol) of 4-chlorobenzoyl chloride and 0.85 ml (6.1 mmol) of triethylamine were added to the obtained solution under cooling with ice, and they were stirred under cooling with ice for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 100 ml of ethanol. 5.3 g (23.5 mmol) of tin chloride was added to the obtained solution, and they were stirred at 70° C. overnight. The solvent was evaporated. Sodium carbonate and ethyl acetate were added to the residue, and they were vigorously stirred at room temperature. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.