Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].CO.[C:6]12([C:16]3[CH:36]=[CH:35][C:19]([C:20]([CH2:22][O:23][C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[I:34])[C:27]([O:29][CH3:30])=[O:28])=O)=[CH:18][C:17]=3[O:37][CH3:38])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[Br-].[CH3:40]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[I:34][C:33]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:23][CH:22]=[C:20]([C:19]1[CH:35]=[CH:36][C:16]([C:6]23[CH2:13][CH:12]4[CH2:14][CH:8]([CH2:9][CH:10]([CH2:11]4)[CH2:15]2)[CH2:7]3)=[C:17]([O:37][CH3:38])[CH:18]=1)[CH3:40]
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(I)c(OCC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OC)c2)c1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(I)c(OC=C(C)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OC)c2)c1

Procedure:
A solution of 30% sodium methoxide in methanol (0.3 ml, 1.6 mmol) is added over 8 hours to a mixture of methyl 3-[4-(1-adamantyl)-3-methoxybenzoylmethyloxy]-4-iodobenzoate (870 mg, 1.55 mmol) and methyltriphenylphosphine bromide (790 mg, 2.21 mmol) in THF (10 ml).
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[CH2:4][CH2:3][CH2:2][C:1]2=[O:6])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCO1
Reactant: Nc1cccc2cccnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCN1c1cccc2cccnc12
Reaction time: 2 h

Procedure:
A mixture of γ-butyrolactone (9.5 g), technical grade 8-aminoquinoline (14.4 g), p-toluenesulphonic acid monohydrate (1.90 g) and mixed xylenes (15 ml) were refluxed with a Dean Stark trap prefilled with xylenes. After one hour γ-butyrolactone (9.0 g) was added and reflux was resumed for two hours. The residue obtained by concentration by vacuum distillation (≃15 mm Hg) of the reaction mixture was extracted with hot ethyl acetate (100 ml). The solid which formed upon cooling the ethyl acetate solution was recrystallized from acetone giving 1-(8-quinolyl)-2-pyrrolidinone, (m.p. 119°-123°), identical by tlc with the product of Example 1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C#N)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (73 mg, 89%), MS (ISP) m/z=327.5 [(M+H)+], mp 323° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([O:33]CC)=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.24 g) and 1N NaOH (1.5 ml) in ethanol (4 ml) was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was extracted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallization of the crystals from ethyl acetate-methanol afforded colorless crystals (0.15 g, 67%), m.p. 183°-185° C.
Reaction SMILES: [F:1][CH:2]([F:21])[C@@:3]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][CH:5]=[O:6].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:19][C:17]([S@@:15]([NH:14][C@:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])([CH2:4][C@@H:5]([OH:6])[C:23]([F:25])([F:24])[F:22])[CH:2]([F:1])[F:21])=[O:16])([CH3:18])[CH3:20]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)[S@](=O)N[C@@](CC=O)(c1ccccc1F)C(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@](C[C@@H](O)C(F)(F)F)(c1ccccc1F)C(F)F
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Intermediates XVII-1 and XVII-2: In a dry flask under an inert atmosphere a solution of (S)—N—((S)-1,1-difluoro-2-(2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (XVI-1) (1.45 g, 4.51 mmol) in THF (30 ml) was treated at 0° C. with (trifluoromethyl)trimethylsilane (1.28 g, 1.33 ml, 9.02 mmol) and dropwise with TBAF (1 M in THF, dried over molecular sieves 4 Å; 0.451 ml, 0.451 mmol). The slightly exothermic addition was completed within 3 min, thereafter the reaction mixture was stirred at 0° C. for 3 h, then left to warm to r.t. and stirred overnight. For the workup, the reaction mixture was quenched with a saturated solution of NH4Cl and extracted three times with AcOEt. The organic layers were washed with brine, dried over MgSO4 and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel (eluent: heptane/AcOEt; gradient: 0-90% AcOEt) to yield the (S)-2-methyl-N-((2S,4R)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (XVII-1) (yellow oil, 377 mg as an approximately 7:3-mixture with its O-trimethylsilyl derivative) as the faster eluting epimer, the (S)-2-methyl-N-((2S,4S)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (XVII-2) (yellow solid, 209 mg, 12% yield) as the second eluting epimer [MS: m/z=392.5 (M+H)+], and the starting aldehyde (yellow oil, crystallized on standing, 627 mg, 36% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26](Br)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:13])([F:12])[F:1])[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1ncc2cc(Br)sc2c1O
Product: CCOC(=O)c1ncc2cc(-c3ccccc3C(F)(F)F)sc2c1O

Procedure:
The title compound was prepared from 2-(trifluoromethyl)phenyl boronic acid and 2-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester, example 21.d, under conditions analogous to experimental example 21.e; MS: (+) m/z 367.9 (M+1)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[CH2:29][CH2:28][O:27][C:26]2=[C:30]([C:33](O)=[O:34])[S:31][CH:32]=[C:25]12>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:30]2[S:31][CH:32]=[C:25]3[C:26]=2[O:27][CH2:28][CH2:29][O:24]3)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1scc2c1OCCO2
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2scc3c2OCCO3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-Dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=516.3.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:8]=2[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:15]([N:11]1[C:12]2[CH2:13][CH2:14][N:5]([CH2:4][CH2:3][OH:2])[CH2:6][CH2:7][C:8]=2[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of [1-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-acetic acid methyl ester (Example 170, 16 mg) in THF (1 mL) was added lithium aluminum hydride (100 mg). The mixture was stirred at RT for 16 h. The reaction was quenched by the addition of H2O (0.1 mL). Concentration and purification (SiO2, 2 M NH3 in MeOH/CH2Cl2) provided the title compound (5 mg). MS (ESI): exact mass calculated for C22H24ClN3O, 381.16. found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.50-7.20 (m, 7H), 7.04 (d, J=7.2 Hz, 1H), 5.29 (s, 2H), 3.07-3.04 (m, 2H), 2.89-2.77 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.N([O-])=O.[Na+].[N:24]#[N:25]>O.C(O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8])=[N+:24]=[N-:25]
Reactant: N#N
Reactant: COC(=O)C(c1ccc(O)c(N)c1)C1CCCC1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C(c1ccc(O)c(N=[N+]=[N-])c1)C1CCCC1

Procedure:
5.0 g (20 mmol) of the crude product from Example XII are dissolved in 20 ml of H2O, 10 ml of ethanol and 20 ml of conc. HCl and the solution is diazotised at 0° C. with 1.8 g (26 mmol) of sodium nitrite in 10 ml of H2O. After evolution of N2 has ended, the mixture is extracted three times with 100 ml of CH2Cl2, the organic phases are concentrated and the residue is chromatographed on silica gel 60 (CH2Cl2 /MeOH=100:2).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:12])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1ccc2cn[nH]c2c1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: Cc1ccc2cn(C)nc2c1Br
Temperature: 80 °C

Procedure:
To a solution of 7-bromo-6-methyl-1H-indazole (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 eq.) was added and reaction was heated at 80° C. for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][N:20]([CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C(c2ccccc2)c2ccccc2)cn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
11 mg (0.23 mmol, 50%) of sodium hydride were added to a solution of 50 mg (0.19 mmol) of ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (example 1g) in 0.5 ml of DMF at RT and stirred for 1 h. Then 48 mg (0.19 mmol) of bromodiphenyl-methane were added, and the mixture was stirred at RT for 3.5 h. It was then heated at 60° C. for 2 h and, after cooling, 1 ml of water was added, the mixture was extracted with EA, and the organic phase was dried over Na2SO4, filtered and concentrated. Chromatography on silica gel afforded ethyl 3-(6-aminopyridin-3-yl)-2-(1-benzhydryl-1H-imidazol-4-yl)propionate. The product obtained in this way was taken up in 0.4 ml of 50% concentrated hydrochloric acid and treated in a microwave at 180° C. for 3 min. Freeze-drying after cooling of the reaction mixture afforded 5 mg of the title compound as bishydrochloride.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[CH:10]([N:8]1[CH2:9][CH:6]([O:5][C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1cccc(F)c1
Product: Fc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Yield: 80.9 %

Procedure:
The title compound (D22) (1.93 g) was prepared according to the experimental procedure described in Description 21 starting from 1-benzhydrylazetidin-3-yl methanesulfonate (D19) (2.5 g, 7.87 mmol) and 3-fluorophenol (0.642 ml, 7.16 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:27]=[C:26]4[O:28][CH2:29][C:23]5[C:24]6[C:25]4=[C:16]([CH2:17][O:18][C:19]=6[CH:20]=[C:21]([C:30]4[NH:34][C:33]([C@@H:35]6[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]6[C:41](=[O:54])[C@H:42]([NH:49][C:50](=[O:53])[O:51][CH3:52])[C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[N:32][CH:31]=4)[CH:22]=5)[CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:55][O:56][C@H:57]([CH3:67])[C@H:58]([NH:62][C:63]([O:65][CH3:66])=[O:64])[C:59](O)=[O:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:66][O:65][C:63]([NH:62][C@@H:58]([C@H:57]([O:56][CH3:55])[CH3:67])[C:59]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:9]1[NH:10][C:11]([C:14]2[CH:27]=[C:26]3[O:28][CH2:29][C:23]4[C:24]5[C:25]3=[C:16]([CH2:17][O:18][C:19]=5[CH:20]=[C:21]([C:30]3[NH:34][C:33]([C@@H:35]5[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]5[C:41](=[O:54])[C@H:42]([NH:49][C:50](=[O:53])[O:51][CH3:52])[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[N:32][CH:31]=3)[CH:22]=4)[CH:15]=2)=[CH:12][N:13]=1)=[O:60])=[O:64]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Reaction time: 1 h

Procedure:
A mixture of methyl (R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (90 mg, >0.123 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (26 mg, 0.135 mmol), HATU (51 mg, 0.135 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1 hour. An additional 0.135 mmol of (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid and HATU were added and stirring continued for 3 hours. The crude product was purified by reverse phase HPLC to product (22 mg) as a trifluoroacetate salt.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([N:18]([CH3:22])[C:19](Cl)=[O:20])[CH3:17]>>[CH3:22][N:18]([CH2:16][CH3:17])[C:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[CH2:9]2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CCN(C)C(=O)Cl
Reactant: Oc1ccc2c(c1)CN(CC1CC1)CC2
Product: CCN(C)C(=O)Oc1ccc2c(c1)CN(CC1CC1)CC2
Yield: 50 %

Procedure:
7-Hydroxy-N-cyclopropylmethyl-1,2,3,4-tetrahydroisoquinoline (9) was mixed homogeneously with N-ethyl-N-methyl-carbamoyl chloride (10a) and carried out step (f-2). Purified on a silica gel column (DCM/MeOH=10:1) gave cyclopropylmethyl- and N-Ethyl-N-methyl amino-containing 7-(N-Methyl-N-ethyl-carbamoyloxy)-N-cyclopropylmethyl-1,2,3,4-tetrahydroisoquinoline (12a) (Yield 50%). 1H NMR (300 MHz, CDCl3) (NMR, Varian Gemini): δ 7.06 (d, J=8 Hz, 1H, Aryl H); 6.84 (s, 1H, Aryl H); 6.81 (s, 1H, Aryl H): 3.71 (s, 2H, Ph-CH2—N); δ 3.44, 3.39 (dd, J=7 Hz, 2H, CH3—N—CH2CH3); 3.03-2.75 (m, 7H, CH3—N—CH2—CH3, Ph-CH2—CH2—N); 2.42 (d, J=6 Hz, 2H, N—CH2); 1.24-1.17 (m, 3H, —CH3); 1.14-0.94 (q, J=7 Hz, 1H); 0.58-0.52 (m, 2H); 0.19-0.14 (m, 2H); IR (KBr): ν cm−1=2924, 1715. Fast Atom Bombardment Mass Spectrometry (FABMS) m/z: 289 (M+1) (C17H24N2O2).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][N:15]=1>C(O)(=O)C>[C:1]([O:4][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][N:15]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1-c1cc(-c2ccccc2)on1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccccc1-c1cc(-c2ccccc2)on1

Procedure:
A mixture of 12.5 g. potassium acetate (0.128 mole), 20.1 g. (0.064 mole) α-bromo-o-(5-phenyl-3-isoxazolyl)toluene and 200 ml. acetic acid is refluxed for 22 hours. The mixture is cooled and the acetic acid evaporated in vacuo. The residue is distilled on high vacuum and the fraction distilling at 140°-150° C. (0.25 mm) is collected and then crystallized from peteroleum ether containing a small amount of ether to give o-(5-phenyl-3-isoxazolyl)benzyl acetate; m.p. 50° to 62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]=O)[C:5]([OH:7])=[O:6].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].C1C=CC=CC=1>O>[Cl:1][CH:2]1[C:10](=[C:11]=[N:17][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3]1
Reactant: CCCCN
Reactant: O=Cc1ccc(C(=O)O)cc1Cl
Solvent: c1ccccc1
Solvent: O
Product: CCCCN=C=C1C=CC(C(=O)O)=CC1Cl

Procedure:
3-Chloro-4-formylbenzoic acid (5 g, 0.027 mole), butylamine (2 g, 0.027 mole) and benzene (75 ml) were refluxed for 2 hours using a flask fitted with a Dean-Stark water separator. The solvent was removed by distillation in vacuo to give 3-chloro-4-(butyliminomethylene) benzoic acid to which was added nitropropane (8.9 g, 0.1 mole) and acetic acid (21 ml). The mixture was refluxed for 10 minutes then cooled in ice. The mixture was treated with water and the solid that separated removed by filtration, washed with water, dried and recrystallized from a mixture of acetic acid and water (2:1) to give 4.7 g of the desired product, m.p. 179°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:23][CH2:24][O:25][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:26][CH3:27])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
To 7.0 g (15.6 mmol) 2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol in 20 ml DMF were added 1.9 g (28.0 mmol, 1.8 eq) imidazole, followed by 3.3 g (21.8 mmol, 1.4 eq) tert-butyldimethylchlorosilane in 20 ml DMF at 0° C. The solution was stirred at 50° C. for 6 h, and at RT for 48 h. Additional 235 mg (1.5 mmol, 0.1 eq) tert-butyldimethylchlorosilane were added and the solution was stirred at 50° C. for 2 h. The solution was poured on an aqueous solution of NaHCO3. The inorganic layer was extracted with ether, and the combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 95:5 gave 6.5 g (74%) {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amine as brown oil, MS: 563 (MH+,1Br).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1B(O)O)([O-:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]3)=[CH:4][CH:3]=2)=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=1
Reactant: Cc1ccc(B(O)O)c([N+](=O)[O-])c1
Reactant: CSc1ncc2ccc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc2ccc(-c3ccc(C)cc3[N+](=O)[O-])n2n1
Temperature: 95 °C

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (600 mg, 2 mmol), 2-nitro-4-methyl-phenylboronic acid (500 mg, 3 mmol) 1.50 M of Sodium carbonate in Water (5 mL, 8 mmol) and dioxane (10 mL) were added to a RB flask. The reaction mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.1 mmol) was added and the reaction mixture was degassed again. The reaction mixture was heated at 95° C. overnight under argon. MS showed product formation. The mixture was cooled to RT, concentrated, filtered through a pad of celite, and partitioned with water and EtOAc. The organic phase was separated, washed with brine, and dried over magnesium sulfate. After solvent evaporation, the product, 7-(4-Methyl-2-nitro-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine, was obtained as a solid which was further purified by taking in ether followed by filtration and washing with ether (628 mg, 80%). LCMS (E/I+) 301 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[CH:8]=2)[CH:3]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
2-Bromo-6-hydroxynaphthalene (100.0 g, 0.45 mol) and imidazole (75.0 g, 1.10 mol) were dissolved in 300 mL of DMF. To this solution was added TBDMS-Cl (80.0 g, 0.53 mol). The reaction was stirred at room temperature under nitrogen overnight. The reaction was poured into water, and the precipitate was filtered, washed with water and cold ethanol. The crude product was recrystallized from ethanol to give 97.2 g of off-white crystals (64% yield). 1H NMR (CDCl3) δ ppm: 0.24 (s, 6H), 1.01 (s, 9H), 7.07 (dd, J1=8.8 Hz, J2=2.3 Hz, 1H), 7.14 (s, 1H), 7.45 (dd, J1=8.8 Hz, J2=2.3 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.90 (s, 1H). 13C NMR (CDCl3) δ ppm: −4.34, 18.24, 25.68, 114.86, 117.26, 123.05, 128.29, 128.42, 129.39, 129.57, 130.24, 133.04. Mp 62-64° C. FD-MS: 337 (M+).