Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:51]>>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([N:55]6[CH2:56][CH2:57][N:52]([CH2:50][CH3:51])[CH2:53][CH2:54]6)=[O:36])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(C(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)cc2)CC1
Yield: 67.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (48.0 mg, 0.0728 mmol) obtained in Step A in Example 1-D-19 and N-ethylpiperazine (37.0 μl, 0.291 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-ethyl-piperazin-1-yl)-methanone as a brown solid (37 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-83) as a yellow powder (25.0 mg, 67%).
Reaction SMILES: C([O-])=O.[NH4+:4].[Cl:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7]([O:9][CH3:10])=[O:8]>C(O)C>[NH2:4][C:11]([CH2:12][CH3:13])=[C:6]([Cl:5])[C:7]([O:9][CH3:10])=[O:8]
Reactant: [NH4+]
Reactant: CCC(=O)C(Cl)C(=O)OC
Agent: O=C[O-]
Solvent: CCO
Product: CCC(N)=C(Cl)C(=O)OC
Yield: 72 %

Procedure:
A solution of 47.5 g (0.75 mol) of ammonium formate and 49.0 g (0.3 mol) of methyl 2-chloro-3-oxovalerate in 800 ml of ethanol is reacted and worked up in analogy to Example 2. Yield: 72.0% [GC]
Reaction SMILES: CN1CCOCC1.[O:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][CH2:21][C:22]([OH:24])=O.ClC(OCC)=O.[N+:35](=[CH2:37])=[N-:36]>C1COCC1>[N+:35](=[CH:37][C:22](=[O:24])[CH2:21][CH2:20][C:12]1[NH:13][C:14]2[C:19]([C:11]=1[CH2:10][C:9]([O:25][CH2:26][CH2:27][CH3:28])=[O:8])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N-:36]
Reactant: CCCOC(=O)Cc1c(CCC(=O)O)[nH]c2ccccc12
Reactant: C=[N+]=[N-]
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCOC(=O)Cc1c(CCC(=O)C=[N+]=[N-])[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
N-methylmorpholine (1.1 equiv.) was added dropwise over 1 h to a stirred, 0° C. mixture of 3-[3-(2-oxo-2-propoxyethyl)-1H-indol-2-yl]propanoic acid from Step 3 and ethyl chloroformate (1.11 equiv.) in THF (0.4 M). The reaction temperature was closely monitored during the addition and was not allowed to go over +2° C. The mixture was stirred at 0° C. an additional 30 min. A white precipitate formed rapidly. Diazomethane (0.3 M in Et2O, 1.8 equiv.) was added and the final mixture was stirred for 2 h at 0° C. The mixture was filtered and the supernatant was concentrated under vacuum (with AcOH put in the vacuum trap to quench excess diazomethane). The residue was purified by column chromatography on silica gel using automatized gradiant pump system CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hexane(10:90 to 60:40) to give the title compound (63%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:17]([NH:19][C:20]1([C:31]#[N:32])[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21]1)=[O:18]>>[C:31]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:24][CH2:23][N:22]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:21]1)#[N:32]
Reactant: N#CC1(NC(=O)C(N)CC2CCCCC2)CCN(C2CCCCC2)C1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CCN(C2CCCCC2)C1

Procedure:
The title compound was prepared starting from 3-chloro benzo[d]isothiazol 1,1-dioxide and 2-amino-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 10, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 40% acetonitrile in water to acetonitrile. MS, m/z 512=M+1.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:41])=[C:5]([C:32]([O:39]C)=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[C:11]([CH:25]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:36][O:35][C:34]1[C:3](=[O:2])[C:4]([CH3:41])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[C:11]([CH:25]=2)[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)=[O:13])[C:32](=[O:39])[C:33]=1[O:37][CH3:38]
Reactant: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.6 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]-4-trifluoromethylaniline (60 mg, 0.1060 mmol) was dissolved in a mixed solvent of acetonitrile (9 ml) and water (3 ml), then CAN (228 mg, 0.4237 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (18 mg, 0.0335 mmol, 32%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][C@H:47]1[CH2:52][CH2:51][C@H:50]([OH:53])[CH2:49][CH2:48]1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:46]([CH:47]3[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:13]=2[S:14][C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Reactant: N[C@H]1CC[C@H](O)CC1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(C2CCC(O)CC2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 52.2 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylic acid (3.19 g, 5 mmol) and trans-4-aminocyclohexanol (1.44 g, 12.5 mmol) gave the title compound (1.80 g, 52%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.81 min; [M+H]+=492.2.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][S:7][C:6](=[S:9])[N:5]1[C:10](=[O:12])[CH3:11])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:28][C@H:22]([CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27])[CH2:11][C:10]([N:5]1[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][S:7][C:6]1=[S:9])=[O:12]
Reactant: C=CCCCC=O
Reactant: CC(=O)N1C(=S)SC[C@H]1C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC[C@@H](O)CC(=O)N1C(=S)SC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
A solution of (R)-1-(4-isopropyl-2-thioxothiazolidin-3-yl)ethanone (11.8 g, 58.1 mmol) in dichloromethane (380 mL) under an atmosphere of nitrogen was cooled to −78° C., titanium tetrachloride (6.37 mL, 58.1 mmol) was added, and the mixture was stirred for 10 min. Diisopropylethylamine (10.12 mL, 58.1 mmol) was added, and the mixture was stirred for 1 h at −78° C. A 1 M solution of hex-5-enal (58.1 mL, 58.1 mmol) in dichloromethane was added, and the mixture was stirred for 2 h at −78° C. The reaction was quenched by addition of half-saturated NH4Cl (30 mL) and warmed to room temperature. The mixture was extracted twice with dichloromethane, and the organic phase was dried and evaporated to provide a residue. Chromatography on silica gel afforded the title compound (12.92 g, 74%). This procedure has also been carried out using the (R)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone auxiliary, with a similar result.
Reaction SMILES: [CH3:1][C:2]12[O:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][O:7]1)[CH2:4][O:3]2.CS(C)=O.[OH-].[K+].[CH2:18](Br)[C:19]#[CH:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]12[O:3][CH2:4][C:5]([CH2:10][O:11][CH2:20][C:19]#[CH:18])([CH2:6][O:7]1)[CH2:8][O:9]2
Reactant: CC12OCC(CO)(CO1)CO2
Reactant: C#CCBr
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: C#CCOCC12COC(C)(OC1)OC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
Compound 6 (5.434 g, 33.9 mmol) was added to a stirring solution of anhydrous DMSO (30 mL) and powdered KOH (7.6 g, 135.7 mmol). After stirring for 10 minutes, the reaction mixture was cooled in an ice bath (0° C.). Propargyl bromide (4.04 g, 3.02 mL, 33.93 mmol) was added drop-wise, the reaction became dark brown rapidly. The reaction was stirred at room temperature for 95 minutes and poured into ice-cold water (200 mL). The product, an off-white solid, was collected by vacuum filtration, and washed with water, dried in vacuo to obtain the analytically pure product. X-ray quality crystals were obtained by slow evaporation from chloroform. Yield: 81%, 5.44 g. 1H NMR (CDCl3; 500 MHz) δ ppm: 1.456 (s, 3H, CH3), 2.442 (t, 1H, CCH), 3.286 (s, 2H, CCH2O), 4.006 (s, 6H, (CH2)3C), and 4.094 (d, 2H, OCH2CCH). 13C NMR (CDCl3; 125.8 MHz) δ ppm: 23.56 (CH3), 34.85 (CH2CCH2), 58.88 (OCH2CCH), 68.12 (CCH2O), 69.55 (OCH2C), 75.34 (CH), 78.97 (CH2CCH), 108.72 (OCCH3). ESI-MS (m/z): 199.10 (199.09 calc'd for C10H14O4 [M+H]+). Elemental analysis calc'd (found) for C7H12O4: C, 60.59 (59.06); H, 7.12 (7.23).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH:2]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1)=[O:1]
Reactant: CCOC(=O)C[C@H]1CC[C@H](CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C

Procedure:
To a 0° C. solution of ethyl [trans-4-(hydroxymethyl)cyclohexyl]acetate (102. 8 mg, 0.514 mmol) in CH2Cl2 (6 n-L) was added Dess-Martin periodinane. The reaction was warmed to room temperature and stirred for several hours. The reaction was then diluted with EtOAc (50 mL) and washed with 1N NaOH and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded ethyl (trans-4-formylcyclohexyl)acetate. Rf=0.57 (40% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 9.61 (d, J=1.4 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 2.13-2.22 (m, 3H), 1.98-2.01 (m, 2H), 1.87-1.91 (m, 2H), 1.77 (m, 1H), 1.31 (qd, J=13.0, 3.4 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H), 1.05 (qd, J=13.0, 3.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([F:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]#[N:21])=[O:14]>>[F:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:12][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]#[N:21])=[O:14])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: NC12CCC(F)(CC1)CC2
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(F)(CC1)CC2
Yield: 76.4 %

Procedure:
Using 4-amino-1-fluorobicyclo[2,2,2]octane (50.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (73.5 mg), the same procedure was followed as in Example 10 to obtain (2S)-1-[[N-(4-fluorobicyclo[2,2,2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (72.3 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[CH:6]1([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7]1.Cl>ClCCl>[CH:6]1([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:1](=[O:3])[CH3:2])=[CH:12][CH:11]=2)[CH2:8][CH2:7]1
Reactant: CC(=O)Cl
Reactant: c1ccc(SC2CC2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(SC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
To dichloromethane (6.7 mL), acetyl chloride (189 μL, 2.66 mmol) and alminium chloride (267 mg, 2.0 mmol) were added sequentially at 0° C., and the mixture was stirred at 0° C. for 10 minutes. Then, a solution of cyclopropyl(phenyl)sulfane (200 mg, 1.33 mmol) in dichloromethane (890 μL) was added, and stirred at 0° C. for 0.5 hours. The reaction solution was added 5% aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and 1-(4-(cyclopropylthio)phenyl)ethanone (181 mg (yield 71%)) was obtained as a colorless oil.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:30])[C:15]2[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17][NH:18][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1.O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1>C(Cl)Cl.[O-2].[Cr+6].[O-2].[O-2]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:15]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:18][NH:17][C:16]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
Pyridine (481.6 g, 6.08 moles) was added dropwise over 35 minutes to a mechanically stirred suspension of chromium (VI) oxide (304.56 g, 3.05 moles) (WARNING: adding pyridine to chromium (VI) oxide is an extremely dangerous procedure and, therefore, chromium (VI) oxide should preferably be added to pyridine) and methylene chloride (6 L) under N2. The reaction as stirred for 40 minutes after pyridine addition was completed and then a solution of diethyl 4-[(4-chloro-2-nitrophenyl)hydroxymethyl]-1H-pyrazole-3,5-dicarboxylate (202.5 g, 0.507 mole) in methylene chloride (1.3 L) was added dropwise over 0.5 hours at room temperature. Stirring at room temperature was continued overnight. CELITE™ (205 g) and additional Collins reagent [chromium (VI) oxide (50g, 0.5 mole) and pyridine (120.3 g, 1.52 moles; methylene chloride (1 L)] were added and the reaction mixture was stirred for 4 days. The reaction mixture was filtered. The filter cake was washed with methylene chloride (3 L) and filtered. The filtrate and wash liquors were combined and concentrated under water aspirator vacuum. The residue was dissolved in ethyl acetate (2 L) and this solution was filtered through a short column of silica gel (3 L). The filtrate was concentrated under water aspirator vacuum. The solid residue was dissolved in warm toluene (800 mL) and then hexane (800 mL) was added with stirring. The mixture was allowed to cool to room temperature and was then filtered. The filter cake was washed with hexane (2×500 mL), and dried under vacuum at 50° C. to give the title compound as a white powder (186.08 g, 93%).
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:30]1[CH2:35][N:34]2[CH2:36][CH2:37][CH:31]1[CH2:32][CH:33]2[C:38]([O:40][CH3:41])=[O:39]>CCOCC>[CH3:41][O:40][C:38]([CH:33]1[CH2:32][CH:31]2[CH2:37][CH2:36][N:34]1[CH2:35][C:30]2=[CH:7][O:8][CH3:9])=[O:39]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CC2CCN1CC2=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC=C1CN2CCC1CC2C(=O)OC
Reaction time: 2 h
Yield: 59.2 %

Procedure:
n-Butyllithium (13,67 ml of a 1.5M solution; 20.5 mmol) was added at 20° to a suspension of methoxymethyltriphenyl phosphonium chloride (7 g, 20.5 mmol) stirred in ether (150 ml) under nitrogen. After 2 h, the mixture was cooled to -35° and a solution of methyl 5-oxoquinuclidine-2-carboxylate (3 g, 16.4 mmol; prepared as described in Zhur. Obshchei. Khim., (1960), 30, 519;see Chem. Abs. (1960), 54: 24723) in ether (20 ml) added. The mixture was allowed to warm to 20° over 1 h and then stirred at this temperature for 16 h. After removing the precipitated triphenylphosphine oxide by filtration, the ether was evaporated off and the resulting oil subjected to chromatography on silica in 3% methanol in dichloromethane to afford the title compound (2.05 g) as a mixture of isomers: m/e 211 (M+); δ(360 MHz, CDCl3) 1.2-2.0 (4H, m, 2×CH2); 2.18-2.34 (1H, m, 4-CH); 2.5-3.4 (5H, m, 2×NCH2 and NCH); 3.50-3.56 (3H, m, OCH3); 3.78-3.82 (3H, m, CO2CH3) and 5.73-5.83 (1H, m, CH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].I[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>CS(C)=O.[Cu]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: Cc1ccc(O)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 210 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4.36 g of 4-methyl-phenol in 70 ml of dry dimethylsulfoxide under nitrogen with stirring is added 9.0 g of potassium t-butoxide. After stirring for 15 minutes, 0.1 g of copper metal is added followed by 10.0 g of 4-iodobenzoic acid. The reactants are stirred under nitrogen while heating at 210° C. for 18 hours. The cooled reaction mixture is extracted with chloroform (2×900 ml) and the remaining water acidified with 2N HCl (pH=3) with ice bath cooling, to give 8.1 g of the desired product. MS(M+H=229.0)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:12](Br)[C:13]#[CH:14].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:13]#[CH:12])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: C#CCBr
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCOc1ccc(S(C)(=O)=O)cc1

Procedure:
A mixture of 4-methylsulfonyl-phenol, propargyl bromide and K2CO3 was refluxed overnight. After cooling, the mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. The crude solid product was purified on silica gel to give the desired product as a pale yellow solid. 1H NMR (CDCl3): δ 7.9 (2H, d), 7.12 (2H, d), 4.79 (2H, d), 3.05 (3H, s), 2.58 (1H, t).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][C:20](NCCO)=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:26]=[N:27][N:28]=[C:11]2[CH2:10][N:9]=1.NC1C=CC2N3C=NN=C3CN=C(C3C=CC=CC=3[Cl:49])C=2C=1>C(Cl)Cl>[Cl:49][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:26]=[N:27][N:28]=[C:11]2[CH2:10][N:9]=1
Reactant: O=C(NCCO)Nc1ccc2c(c1)C(c1ccccc1F)=NCc1nncn1-2
Reactant: Nc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nncn1-2
Solvent: ClCCl
Product: O=C=Nc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nncn1-2

Procedure:
A solution of [6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-8-yl]isocyanate is prepared as described in paragraph (a) of Example 1 from 7.0 g (22.6 mmol) of 8-amino-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine, but using methylene chloride in place of 1,2-dichloroethane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].[H-].[Na+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:21])[CH:14]=[C:13]([C@@H:22]([NH:24][C:25]2[N:33]=[CH:32][N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][N:29]3C(OC(C)(C)C)=O)[CH3:23])[N:12]=1.O>C1COCC1>[N:33]1[C:25]([NH:24][C@H:22]([C:13]2[N:12]=[C:11]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:21])[CH3:23])=[C:26]2[C:30]([NH:29][CH:28]=[N:27]2)=[N:31][CH:32]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C(=O)OC(C)(C)C)c1cc2cccc(Cl)c2c(Cl)n1
Reactant: CC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCOc1nc([C@H](C)Nc2ncnc3[nH]cnc23)cc2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of N-(2-hydroxyethyl)acetamide (110 mg, 1.07 mmol, 2.43 eq) in THF (20 mL) at 0° C., NaH (60% in mineral oil, 110 mg, 2.75 mmol, 6.25 eq) was added and the resulting mixture was stirred for 15 min. To this mixture, (S)-tert-butyl 6-(1-(1,8-dichloroisoquinolin-3-yl)ethylamino)-9H-purine-9-carboxylate 39 (200 mg, 0.44 mmol, 1.0 eq) was added. The resulting mixture was stirred at reflux for 2 h, cooled to RT and then poured into water (30 mL). The mixture was extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (3% MeOH-DCM) to afford the product (S)—N-(2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1-yloxy)ethyl)acetamide 40. ESI-MS m/z: 426.0 [M+H]+.