Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][N:44]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1ccnc(-c2cc(C)c(Br)c(C)c2)c1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cc(C)ccn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-4-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=538 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[CH2:18][N:19]1[C:27]2[N:26]=[CH:25][NH:24][C:23]=2[C:22](=[O:28])[NH:21][C:20]1=[S:29].C1C(I)=C(OC2C=C(I)C(O)=C(I)C=2)C(I)=CC=1C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:18][N:19]1[C:27]2[N:26]=[CH:25][NH:24][C:23]=2[C:22](=[O:28])[NH:21][C:20]1=[S:29]
Reactant: CC(C)(C)OC(=O)n1cc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)c2cc(Cl)ccc21
Agent: O=C(O)c1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2c[nH]c3ccc(Cl)cc23)c2nc[nH]c12
Yield: 66.3 %

Procedure:
A solution of tert-butyl 5-chloro-3-[(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)methyl]-1H-indole-1-carboxylate (0.043 g, 0.10 mmol, obtained from Example 10(c)) in CH2Cl2:TFA 4:1 (2 mL) was stirred for 3.5 h and then evaporated. Purification of the crude product by preparative HPLC gave the title compound (0.022 g, 68%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH2:27][CH2:28][NH:29][CH2:30][CH:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:29]([CH2:28][CH2:27][OH:26])[CH2:30][CH:31]([OH:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: OCCNCC(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(CCO)CC(O)c2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (75 mg, 0.190 mmol), α-2-hydroxyethylaminomethyl-benzyl alcohol (Bulletin of the Chemical Society of Japan, 56(1), 212-18; 1983)(51 mg, 0.28 mmol) and diisopropylethylamine (50 μL, 0.29 mmol) in dry DMF (4.0 mL) was heated to 60° C. for 18 hours. The solution was then diluted with water (20 mL). The resulting precipitate was collected by filtration and the collected solid was dried in vacuo at 60° C. to provide the titled compound (92 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11](N(OC)CC)=[O:12])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:24][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11](=[O:12])[CH3:24])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: C[Mg]Br
Reactant: CCN(OC)C(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of 2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-N-methoxy-N-ethyl-acetamide (200 mg, 0.60 mmol) in THF (4 mL) at −78° C. was added methylmagnesium bromide (1.28 mL, 1.79 mmol, 1.4 M solution in THF/toluene) and the resulting mixture warmed to RT and stirred for 3 hours. The resulting mixture was quenched with 1M HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 1-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propan-2-one as a white solid (146 mg, 80%). LCMS: RT=2.90 min, [M+H]+=306/308/310.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].C(N(C(C)C)C(C)C)C.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29](O)=[O:30])=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:29](=[O:30])[CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([Br:20])=[CH:26][N:25]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1N
Reactant: O=C(O)COc1ccc(Br)cn1
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: O
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of 4-amino-thiophene-3-carboxylic acid methyl ester (0.5 g, 2.58 mmol) in dimethylformamide (25 mL) was added N-ethyldiisopropylamine (2.25 mL, 12.9 mmol), (5-bromo-pyridin-2-yloxy)-acetic acid ([79674-66-1], 0.6 g, 2.58 mmol) and HATU (Acros 365312, 1.24 g, 3.23 mmol). The reaction mixture was stirred for 2 hours at room temperature. After such time water was added to the reaction mixture until precipitation occurred (sonication was also used to ease precipitation). The precipitate was then isolated by filtration and washed with a mixture of water and ethanol (3:1) to yield the title compound as a light brown solid (0.96 g, 73%).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH:8]=O)[CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:8]=[CH:14][C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cccc(OC2CC2)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(OC2CC2)c1

Procedure:
3-cyclopropoxybenzaldehyde (7.51 g, 46.3 mmol) was dissolved in pyridine (195 mL) then malonic acid (19.3 g, 185 mmol) and piperidine (6.86 mL, 69.5 mmol) were added. The reaction was stirred at reflux for 2 hr then concentrated. The residue was poured on to ice cold 6N HCl and decanted to collect the solution. The solution was diluted with DCM and extracted with DCM. The extract and the solid from the water layer were combined and basified with 2N NaOH. The basic solution was washed with DCM, acidified and filtered to give 3-(3-cyclopropoxy-phenyl)-acrylic acid as white solid: 1H NMR (CDCl3, 300 MHz) δ 7.77 (d, 1H), 7.36-7.09 (m, 4H), 6.44 (d, 1H), 3.77 (m, 1H), 0.81 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].C[O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])=[O:26].Cl>>[C:17]1([S:14]([N:6]2[C:7]3[C:12](=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:4]([C:1](=[O:3])[CH:2]=[C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:25]([OH:26])=[O:24])[CH:28]=3)[OH:31])=[CH:5]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Agent: Cl
Product: O=C(O)c1cccc(C(O)=CC(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(Cl)cc23)c1

Procedure:
In accordance with Example 99, 3-acetyl-1-benzenesulfonyl-5-chloroindole reacted with 3-methoxycarbonyl benzoylchloride, followed by hydrolysis with hydrochloric acid to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7](Cl)=O.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28]>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=2[C:7]2[NH:29][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: Nc1ccccc1N
Reactant: O=C(Cl)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1ccc(Cl)cc1-c1nc2ccccc2[nH]1)c1ccc(Cl)cc1

Procedure:
1.00 g (2.7 mmol) of 5-chloro-2-(4-chloro-phenylsulfonylamino)-benzoyl chloride and 296 mg (2.7 mmol) of o-phenylenediamine in 150 ml of toluene were heated under reflux for 1 h. A small amount of solid was filtered off with suction and the filtrate was evaporated. The residue was taken up in 50 ml of toluene, 600 mg of thionyl chloride were added and the mixture was again heated under reflux for 10 h. Subsequently it was cooled and the precipitated solid was filtered off with suction. 280 mg (25%) of the title compound having a melting point of 225-228° C. were obtained.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][CH:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=351 (M+ of free base). α[D]589 =-15.49(c=0.86, methanol).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C@H:30]1[CH2:36][NH:35]/[C:34](=[N:37]\[CH2:38][CH:39](O)[CH2:40][C:41]([F:44])([F:43])[F:42])/[C@H:33]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:32][CH2:31]1>C(#N)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C@H:30]1[CH2:36][N:35]2[C:39]([CH2:40][C:41]([F:44])([F:43])[F:42])=[CH:38][N:37]=[C:34]2[C@H:33]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2c(F)cccc2F)CN/C1=N\CC(O)CC(F)(F)F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2c(F)cccc2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 18 h

Procedure:
Pyridinium dichromate (2.24 g, 5.94 mmol) was added to a solution of tert-butyl {(2Z,3R,6S)-6-(2,6-difluorophenyl)-2-[(4,4,4-trifluoro-2-hydroxybutyl)imino]azepan-3-yl}carbamate (461 mg, 0.99 mmol) in acetonitrile (20 mL). After 18 h, the mixture was filtered and concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (80% hexanes/ethyl acetate→50% hexanes/ethyl acetate) gave the title compound. MS 446.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:29]C(=O)OC(C)(C)C)[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[C:25]([CH3:28])[CH:26]=[CH:27][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[NH2:29][C@H:11]([C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[C:25]([CH3:28])[CH:26]=[CH:27][N:14]2[N:13]=1)[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccn2nc([C@H](CCOCc3ccccc3)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3ccccc3)c(=O)c12
Yield: 103 %

Procedure:
(S)-tert-Butyl (3-(benzyloxy)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (30 mg, 0.06 mmol) was treated with a solution of hydrochloric acid in dioxane (4M, 230 μl, 0.92 mmol) according to the method described in Preparation 1 to obtain 24 mg (91% yield) of the title compound. Purity 98%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@@H:26]([NH:29]C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21]([C@H:23]2[CH2:24][CH2:25][C@@H:26]([NH2:29])[CH2:27][CH2:28]2)=[O:22])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-(tert-Butoxycarbonyl)-cis-4-amino-1-cyclohexanecarboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (24) (1.80 g; 3.65 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 6 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product. CIMS: MH+ 393
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[N+:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N+:16]([O-])=O)([O-])=O>>[CH3:5][O:4][C:1]([NH:7][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:1]([O:4][CH3:5])=[O:6])=[O:6]
Reactant: O=[N+]([O-])CCCCCC[N+](=O)[O-]
Reactant: COC(=O)OC
Product: COC(=O)NCCCCCCNC(=O)OC
Reaction time: 8 h
Yield: 85 %

Procedure:
In a reinforced glass reactor with a capacity of 5 ml 2 ml of dimethyl carbonate and 150 mg of 1,6-dinitrohexane and 100 mg of Au/CeO2 (1 wt % gold relative to cerium) are introduced. The reactor is closed and purged with N2 to remove oxygen from the solution. Then the reactor is charged at 15 bars of hydrogen and immersed in a silicone bath preheated at 90° C. The suspension is magnetically stirred for 8 hrs. After this time, the reactor is discharged at atmospheric pressure, opened and the mixture is filtered. A gas chromatography analysis revealed the presence of 1,6-bis (methoxycarbonylamino) hexane in an 85% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[C:18](=[O:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH:18]([OH:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydro-9-(2-methylbenzylamino)acridin-1(2H)-one (4.15 g) was suspended in 100 ml of THF and chilled with ice-water. 1M lithium aluminum hydride in THF (8.0 ml) was added dropwise through a syringe and then the reaction mixture was stirred 30 minutes in the cold. It was quenched by the sequential addition of 0.5 ml of water, 0.5 ml of 15% sodium hydroxide and 1.5 ml of water. The inorganic salts were filtered and the organic phase was evaporated to obtain an amorphous solid product. Recrystallization from ethyl acetate give 3.38 g, mp 167°-169° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][OH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:33]([O:34][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(OCCc3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A mixture of [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.075 g, 0.202 mmol), 2-phenylethanol (0.025 g, 0.202 mmol) and sodium hydride (0.010 g) in 5 mL of toluene was stirred at room temperature for 1 hour, and then refluxed overnight. The reaction mixture was cooled to room temperature, added 20 mL of water, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (58 mg, 62.9%). 1H NMR (400 MHz, CDCl3) δ 7.73, 7.61-7.64, 7.53-7.56, 7.36, 7.22-7.30, 7.20-7.24, 7.02, 6.86, 4.64, 3.91-3.98, 3.57, 3.48-3.52, 3.32, 3.11.
Reaction SMILES: [C:1]1([CH3:15])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C>CS(C)=O>[C:1]1([CH3:15])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1Nc1nc(CO)cs1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1Nc1nc(C=O)cs1

Procedure:
Following a procedure similar to that described in Preparation 44, the desired compound was prepared from 6.12 g of 2-(o-toluidino)thiazole-4-ylmethanol, 13.2 g of a sulfur trioxide pyridine complex, 12 ml of triethylamine and 210 ml of dimethyl sulfoxide, as pale brown prismatic crystals having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH2:13]([C:15]1[CH:16]=[C:17]([CH3:27])[C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:19][CH:20]=1)[CH3:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH2:13][CH3:14])=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Yield: 99.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (2.4 g) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine hydrochloride (2.4 g) described in Preparation Example 99, the title compound (4 g) was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][OH:11].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][O:11][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCN(CCC1OCCO1)Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCN(CCC1OCCO1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-((2-(1,3-dioxolan-2-yl)ethyl)(benzyl)amino)ethanol (2.81 g, 11.2 mmol) in DMF (10 mL) was added imidazole (1.67 g, 24.61 mmol) and tert-butyldimethylsilyl chloride (3.35 g, 22.39 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated art reduced pressure (3.87 g, 95%).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7].NCC[CH2:13][OH:14]>>[OH:14][CH2:13][CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(=O)NCCO
Reactant: NCCCO
Product: NC(=O)C(=O)NCCCO
Yield: 75 %

Procedure:
Prepared as in Intermediate 3, using 3-aminopropanol to give the title compound as a white powder (1.15 g, 75%); NMR [(CD3)2SO] 1.6 (2H, m), 3.18 (2H, m), 3.42 (2H, m), 4.47 (1H, t), 7.73 (1H, br s), 8.0 (1H, br s), and 8.63 (1H, t).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]#[N:18])=[C:8]([Br:19])[C:7]=2[CH:20]=1.Cl[C:22]1[N:27]2[N:28]=[CH:29][CH:30]=[C:26]2[N:25]=[C:24]([CH2:31][CH3:32])[CH:23]=1.[Cl-].C(N(CC)CC)C>C(O)C>[Br:19][C:8]1[C:7]2[CH:20]=[C:3]([CH2:2][NH:1][C:22]3[N:27]4[N:28]=[CH:29][CH:30]=[C:26]4[N:25]=[C:24]([CH2:31][CH3:32])[CH:23]=3)[CH:4]=[CH:5][C:6]=2[O:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: N#Cc1ccccc1-c1oc2ccc(CN)cc2c1Br
Reactant: CCc1cc(Cl)n2nccc2n1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(NCc2ccc3oc(-c4ccccc4C#N)c(Br)c3c2)n2nccc2n1

Procedure:
540 mg (1.65 mmol) 5-(aminomethyl)-3-bromo-2-(2-cyanophenyl)benzofuran (prepared according to WO 92/09600) and 300 mg (1.65 mmol) 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) were heated with reflux in 4 ml dry ethanol for 13 h. In order to complete the conversion of the amine 200 mg of the chloride and 0.24 ml triethylamine in 4 ml dry ethanol were added, and the mixture was heated for additional 21 h. The solvent was removed in vacuo, and the title compound isolated from the residue by chromatography (hexane/acetone 95:5 to 75:25) to give colorless crystals after evaporation to dryness,
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[NH:7][C:6]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:5]1=2)(=[O:3])[CH3:2].Cl[CH2:34][C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[O:45][CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:15])[C:8](=[O:26])[N:7]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][C:36]=2[O:45][CH3:46])[C:6]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2ccccc2c1CCl
Reactant: CC(=O)N1c2cc(C#N)ccc2NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-8-cyano-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (53 mg, 120 μmol) in DMF (299 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (29.6 mg, 143 μmol), cesium carbonate (50.6 mg, 155 μmol), and sodium iodide (23.3 mg, 155 μmol). The reaction was stirred at rt for 1 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (60 mg, 82%) as a white solid. MS m/z 636 (MNa)+.