Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[N:18]([C:27]2[N:28]=[CH:29][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:40])([F:41])[F:39])=[CH:31][N:32]=2)[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A 20-mL vial was charged with tert-butyl (3R)-3-(((methylsulfonyl)(phenyl)amino)methyl)-1-piperazinecarboxylate (0.425 g, 1.15 mmol, step 4), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.411 g, 1.47 mmol, Intermediate D), DIPEA (0.602 mL, 3.45 mmol) and 1,4-dioxane (5 mL). The vial was sealed and the reaction mixture was heated at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature and partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((methylsulfonyl)(phenyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.464 g) as a light-brown solid.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[CH2:26])=[CH:20][CH:19]=1)[N:6]([SiH:14]([CH3:16])[CH3:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[Li+].[OH-]>C1COCC1.O>[C:7]([N:6]([SiH:14]([CH3:16])[CH3:15])[C@H:5]([C:4]([OH:27])=[O:3])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]=[CH2:26])=[CH:22][CH:23]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C=CCc1ccc(C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)[SiH](C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1ccc(C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)[SiH](C)C)cc1
Yield: 79.2 %

Procedure:
The same procedure as described for 5 Scheme 2 was followed except that (Boc)2O was used instead of FmocCl for protection of the amine group; Colorless oil (yield=64%); 1H NMR (300 MHz, CDCl3) δ 0.24 (s, 6 H), 1.19 (t, J=7.14 Hz, 3 H), 1.39 (s, 9 H), 1.72 (d, J=11.1 Hz, 2 H), 3.04 (m, 2 H), 4.13 (t, J=7.14 Hz, 2 H), 4.54 (m, 1 H), 4.79 (m, 1 H), 4.83 (m, 1 H), 5.07 (bd, NH, 1 H); 13C NMR (75 MHz, CDCl3) −3.4 (2C), 14.1, 23.6, 28.3 (3C), 38.4, 54.4, 61.2, 79.7, 113.4, 128.8 (3C), 133.8 (2C), 134.5, 137.0, 155.1, 171.9. (b) N-Boc-4-allyldimethylsilylphenylalanine ethyl ester (190 mg, 0.5 mmol) was hydrolyzed with a LiOH (60 mg, 2.5 mmol) in THF/H2O (5:1, 15 mL) for 4 h at room temperature. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (20 mL). After neutralization of the solution with acetic acid and concentration, the residue was purified by column chromatography (5:1 ethyl acetate/MeOH) to afford a viscous solid (144 mg, 82%); 1H NMR (300 MHz, CDCl3) δ 0.29 (s, 6 H), 1.41 (s, 9 H), 1.76 (d, J=7.68 Hz, 2 H), 3.05-3.32 (2 H), 4.48 (m, 1 H), 4.86 (m, 1 H), 4.91 (m, 1 H), 5.80 (m, 1 H), 7.24 (d, J=7.29 Hz, 2 H), 7.47 (d, J=7.29 Hz, 2 H).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][N:23]3[CH:31]=[CH:32][CH:33]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1)=[O:10]>CN1CCCN(C)C1=O>[CH:33]1[CH:32]=[CH:31][N:23]2[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:20]([C:18]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[CH2:8][N:2]4[CH:6]=[N:5][CH:4]=[N:3]4)=[CH:17][CH:16]=3)=[O:19])[CH2:21][C:22]=12
Reactant: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN1CCCN(C)C1=O
Product: O=C(Cn1cncn1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a suspension of 0.20 g of 1,2,4-triazole sodium in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro2(1H)-pyrimidinone is added 0.10 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone followed by stirring at room temperature for 3 hours. The reaction mixture is quenched with 15 ml of water and the resulting solid is collected, washed with water and hexanes to give 70 mg of the desired product as a tan solid.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[C:22]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][CH2:30][NH:31][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCCc1ccccc1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)NCCCc2ccccc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and 3-phenylpropylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=309.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[C:36]([O:40][C:41](=[O:48])[NH:42][CH2:43][CH:44]1[CH2:47][NH:46][CH2:45]1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41](=[O:48])[NH:42][CH2:43][CH:44]1[CH2:45][N:46]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]3[N:9]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:10]([C:12]4[C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=5)[N:14]([CH3:25])[CH:13]=4)=[CH:11][C:4]=23)[CH2:47]1)([CH3:39])([CH3:37])[CH3:38].[C:36]([O:40][C:41](=[O:48])[NH:42][CH2:43][CH:44]1[CH2:45][N:46]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:9][C:10]([C:12]4[C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=5)[N:14]([CH3:25])[CH:13]=4)=[CH:11][C:4]=23)[CH2:47]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Reactant: COc1cc2c(-c3cc4c(CCl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Product: COc1cc2c(-c3cc4c(CN5CC(CNC(=O)OC(C)(C)C)C5)ccnc4[nH]3)cn(C)c2cc1OC
Product: COc1cc2c(-c3cc4c(CN5CC(CNC(=O)OC(C)(C)C)C5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Yield: 221.9 %

Procedure:
{1-[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-ylmethyl}carbamic acid tert-butyl ester is prepared as described in Example 200b starting with 0.14 g of 4-chloromethyl-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.123 g of azetidin-3-ylmethylcarbamic acid tert-butyl ester instead of the piperid-4-ol used in Example 200b. After purification by flashpack chromatography (SiO2, dichloromethane/methanol 95/5 by volume as eluent), 0.154 g of {1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-ylmethyl}carbamic acid tert-butyl ester is obtained, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:33]1([CH:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.33–7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (t, 2H, J=5.6 Hz), 2.93 (d, 2H, J=11.3 Hz), 2.52–2.36 (m, 4H), 1.97 (t, 2H, J=11.3 Hz), 1.83–1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); Anal. Calcd for C32H39N3O2+HCl+0.19CHCl3: C, 69.44; H, 7.27; N, 7.55. Found: C, 69.44; H, 7.43; N, 7.43; ESMS m/e: 498.4 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].S(O)(=O)(=O)C.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH2:20][O:19]1.ClCCl>O.CN(C)C=O>[N:1]([CH2:20][C:18]([C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[Cl:10])([OH:19])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)=[N+:2]=[N-:3]
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium azide (22.75 g, 0.35 mole) in water (62.5 ml) was added to a solution of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane monomesylate (25 g, 0.068 mole) in dimethylformamide (DMF) (250 ml) and the reaction mixture was stirred at room temperature for 0.5 hours and then at 60° for 16 hours. The reaction mixture was cooled and then poured into a mixture of dichloromethane (250 ml) and water (75 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×25 ml) and the combined organic extracts were then dried (MgSO4), filtered and evaporated. The residue was triturated with diethyl ether and the resulting solid filtered off and then recrystallized from an ethyl acetate-hexane mixture to furnish the title azide as a colorless crystalline solid, (16.9 g, 79%) m.p. 117°-19°.
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)CC(O)=O.[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19].[NH:24](C(OCC1C=CC=CC=1)=O)[C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].C(O)C(N)(CO)CO>>[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: NC(CO)(CO)CO
Agent: O=C(O)CNC(=O)OCc1ccccc1
Product: C[C@H](N)C(=O)O

Procedure:
The title compound was obtained in quantitative yield by hydrogenation of a solution of Z-Gly-Tris in ethanol at 40 atm. pressure in a Parr hydrogenator in the presence of palladium on carbon (10%). The removal of the benzyloxycarbonyl group was monitored by HPLC (System A). The catalyst was removed by filtration and washed with ethanol. Evaporation of the solvent gave the title product in 95% purity as shown by 1H NMR spectroscopy. Ala-Tris was prepared in an analogous manner. The preparation of Z-Gly-Tris and Z-Ala-Tris are described in Whittaker, R. G., Hayes, P. J., and Bender, V. J. (1993) Peptide Research 6, 125 and Australian Patent No. 649242.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:17])[CH:13]=[CH:12]2>N1C=CC=CC=1>[CH3:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][CH:19]=2)[CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=[O:17])[CH:13]=[CH:12]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2ccc(N)cc2)cc2ccc(=O)[nH]c12
Solvent: c1ccncc1
Product: Cc1cc(-c2ccc(NS(C)(=O)=O)cc2)cc2ccc(=O)[nH]c12

Procedure:
Methanesulphonyl chloride (0.15 cm3) was added dropwise to a stirred solution of 8-methyl-6-(4-aminophenyl)-2-(1H)-quinolone (0.47 g) (see Example 13) in pyridine (3 cm3) at room temperature. After 0.5 hours volatile material was removed in in vacuo and the residue was partitioned between water (50 cm3) and dichloromethane:methanol, 4:1 (50 cm3). The insoluble material was filtered off, washed with methanol (10 cm3) and dried to afford the title compound, m.p. 340°-343° (0.45 g).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([CH3:11])[C:4]=2[CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.CO/[CH:45]=[CH:46]/[C:47]([O:49][Si](C)(C)C)=[CH2:48]>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]3[CH:45]=[CH:46][C:47](=[O:49])[CH2:48][CH:7]3[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Reactant: CC1c2ccccc2C=Nc2ccc(Br)cc21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Product: CC1c2ccccc2C2CC(=O)C=CN2c2ccc(Br)cc21
Reaction time: 8 h
Yield: 41 %

Procedure:
To a stirred solution of 2-bromo-11-methyl-11H-dibenzo[b,e]azepine (5R8═Br; 666 mg, 2.33 mmol) ytterbium (III)triflate (146 mg, 0.23 mmol) was added. After stirring for 10 min. at room temperature Danishefsky's diene (0.89 mL, 4.66 mmol) was added. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was quenched with aqueous NaHCO3, extracted into ethyl acetate, washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica to give 8-bromo-10,14b-dihydro-10-methyl-dibenzo[c,f]pyrido[1,2-a]azepin-2(1H)-one (6, R8═Br; 338 mg, 41%). Data: (m/z)=354/356 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([O:22][CH3:23])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:24]1(=O)[C:27]2([CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:26](=[O:33])[CH2:25]1>C(Cl)Cl>[O:33]=[C:26]1[C:27]2([CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:24]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[C:10]([O:22][CH3:23])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([O:14][CH3:15])[CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:25]1
Reactant: O=C1CC(=O)C12CCOCC2
Reactant: COC(=O)[C@@H](N)Cc1cc(OC)c(-c2ccccc2)c(OC)c1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(OC)c(-c2ccccc2)c(OC)c1)NC1=CC(=O)C12CCOCC2
Yield: 84.4 %

Procedure:
Using a similar procedure to that for the preparation the compound of Example 38 from methyl (2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (2.0 g, 6.3 mmol) and 7-oxaspiro[3.5]nonane-1,3-dione (1.1 g, 1.1 eq) in DCM (30 ml) was prepared the title compound as a white foam (2.4 g, 86%). δH (300 MHz, DMSO d6) 8.53 (1H, d, J 8.7 Hz), 7.20–7.30 (3H, m), 7.08 (2H, d, J 8.1 Hz), 6.70 (2H, d, J 8.5 Hz), 4.44 (1H, s), 4.30 (1H, m), 3.72 (3H, s), 3.61 (6H, s), 3.22 (1H, dd, J 13.7, 5.0 Hz), 2.98 (1H, dd, J 13.8, 10.1 Hz), 1.74–1.99 (2H, m), 1.48 (1H, d, J 13.6 Hz), 1.31 (1H, d, J 13.0 Hz); m/z (ES+, 70V) 439 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.C([Li])CCC.[C:12](Cl)(=[O:14])[CH3:13]>O1CCCC1>[CH2:1]([C:2]1[O:3][CH2:4][CH2:5][N:6]=1)[C:12]([CH3:13])=[O:14]
Reactant: CC1=NCCO1
Reactant: CC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)CC1=NCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.5 g. (0.1 mole) of 2-methyl-1,3-oxazoline in 85 ml. of dry tetrahydrofuran, and cooled in an acetone-dry ice bath to -60° C., is added 6.4 g. (0.1 mole) of n-butyl lithium and the reaction mixture allowed to stir for 1 hour. To the cloudy solution is then added 7.8 g. (0.1 mole) of acetyl chloride at such a rate that the temperature is maintained below -50° C. The reaction mixture is allowed to warm to room temperature and is then filtered and the solvent removed in vacuo. The desired product is purified by distillation under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:19]([C:26]([F:29])([F:28])[F:27])=[CH:18][C:16]=1[NH2:17]>ClCCCl>[C:4]([NH2:6])(=[O:5])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:2]=1.[Cl:14][C:15]1[C:21]([C:22]([F:24])([F:25])[F:23])=[CH:20][C:19]([C:26]([F:27])([F:28])[F:29])=[CH:18][C:16]=1[NH:17][C:7]([NH:6][C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=1[F:13])=[O:8]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Cl
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: ClCCCl
Product: NC(=O)c1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Cl

Procedure:
In order to synthesize the isocyanate, 1.57 g (10 mmol) of 2,6-difluorobenzamide and 15 ml of dry 1,2-dichloroethane were introduced into a 100 ml flask and then 0.92 g (10.5 mmol) of oxalyl chloride was slowly added thereto at normal temperature by means of a syringe, during which an exothermic reaction occurred that generated hydrochloride gas. The resulting reaction mixture was refluxed for 5 hours and cooled to normal temperature. The reaction solvent and the excess oxalyl chloride were removed therefrom under vacuo to obtain 2,6-difluorobenzoyl isocyanate in an oily state. Thus obtained 2,6-difluorobenzoyl isocyanate was then dissolved in 20 ml of dry 1,2-dichloroethane. Then, 2.63 g of 2-chloro-3,5-bis(trifluoromethyl)aniline was added thereto, reacted for 3 hours, and filtered to obtain 4.15 g (Yield from benzamide, 93%) of the title compound as a solid.
Reaction SMILES: [CH:1]1([C:7]([NH:9][NH2:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([C:11](=[N:10][NH:9][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH3:12])=[CH:15][CH:16]=1
Reactant: NNC(=O)C1CCCCC1
Reactant: CC(=O)c1ccncc1
Solvent: CCO
Product: CC(=NNC(=O)C1CCCCC1)c1ccncc1
Yield: 73.1 %

Procedure:
A solution of 4.26 gm (0.03 mole) of cyclohexanecarboxylic acid hydrazide, 3.63 gm (0.03 mole) of 4-acetylpyridine and 100 ml of ethanol is refluxed 7 hr. The solvent is evaporated in vacuo to give a white solid. The product is crystallized from ethyl acetate to yield 5.38 gm (73%) of the title compound having a melting point of 195.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([NH:25][C:26]([N:8]1[CH:7]([CH3:20])[CH2:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:9]1)=[O:27])[CH3:24]
Reactant: CCN=C=O
Reactant: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Solvent: Cc1ccccc1
Product: CCNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2CC1C
Yield: 69.4 %

Procedure:
0.6 g (1.9 mmoles) of 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 5, Step D or in Example 36, starting compound) are boiled with 0.75 ml (9.5 mmoles) of ethyl isocyanate in 25 ml of anhydrous toluene for 24 hours. The mixture is evaporated, the residue is recrystallized from 5 ml of ethanol. Thus, 0.51 g (69%) of the title compound are obtained. M.p.: 170°-172° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]([CH:14]3[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:18].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:14][CH2:15][CH2:16][Br:18])=[CH:4][C:3]=2[O:2]1
Reactant: BrP(Br)Br
Reactant: OC(CCc1ccc2c(c1)OCO2)C1CC1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: BrCCC=CCCc1ccc2c(c1)OCO2

Procedure:
[V; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 11.5 g. of 2-(3,4-methylenedioxyphenyl)ethyl cyclopropyl carbinol (Preparation B2), 12 g. of phosphorus tribromide, 10 g. of lithium bromide and 12.7 g. of zinc bromide according to the procedure given above in Preparation C1, affording 12.5 g. of product as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.C(O)C>[Pd].O1CCCC1>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:19])=[CH:15][CH:14]=1
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Yield: 57.4 %

Procedure:
A solution of 4.34 g (0.0165 mole) of N-(1-methyl-piperidin-4-yl)-4-nitro-benzamide, 0.50 g of 10% palladium on carbon catalyst, 200 mL of ethanol and 30 mL of tetrahydrofuran was stirred under an atmosphere of hydrogen for 4 hours. The mixture was then filtered through Celite and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give 2.21 g of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide as off-white crystals.
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3](C(OC(C)(C)C)=O)[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:37]1([N:43]2[CH2:48][CH2:47][N:46]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[O:27])[CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)C(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1CCNCC1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
(1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 2; 5.0 g, 13.1 mmol) was dissolved in DMF (30 mL). DIPEA (4.58 mL, 26.3 mmol) and 1-phenylpiperazine (2.01 mL, 13.1 mmol) were added. The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with sat aq NaHCO3 solution (6×200 mL), 10% citric acid solution (50 mL) and brine (50 mL). The solution was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (20 mL) and TFA (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in water (20 mL), sat aq NaHCO3 solution (100 mL) was added and the aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were then washed with brine (50 mL), dried (MgSO4) and the solution was concentrated in vacuo to give (piperidin-4-yl)methyl 4-phenylpiperazine-1-carboxylate (3.825 g, 95.9% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1)[C:2]#[CH:3].[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:4]([CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)[CH2:1][C:2]#[CH:3])=[O:32])[CH2:28][CH2:29]2)=[O:23])=[CH:34][CH:35]=1
Reactant: C#CCNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: C#CCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following the general procedure of Example 4, the title compound was prepared (44.3 mg) from 2-((prop-2-ynylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C25H27FN4O4 466.5. found 467.7 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.98 (dd, J=9.09, 5.56 Hz, 2H) 7.20 (t, J=8.59 Hz, 2H) 4.67 (d, J=9.60 Hz, 2H) 4.51 (d, J=15.16 Hz, 2H) 4.26-4.41 (m, 3H) 4.22 (br. s., 2H) 3.88-4.01 (m, 4H) 2.63-2.85 (m, 2H) 2.32 (br. s., 1H) 2.24 (br. s., 4H) 1.46-1.58 (s, 2H).