Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:38])=[N:4][O:5][C:6]=1[N:7]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](O)[C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH3:30])(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:38])=[N:4][O:5][C:6]=1[N:7]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH3:30])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 82 %

Procedure:
The title compound was prepared by the method of Example 5(A), using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-2-methyl-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.16 g, 0.28 mmoles), CH2Cl2 (3 ml), triethylsilane (0.45 ml, 2.8 mmoles) and boron trifluoride etherate (0.17 ml, 1.4 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.13 g (82%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[N:11]O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[H][H]>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1cccc(C(C)=NO)c1
Agent: [Ni]
Solvent: CO
Product: COc1cccc(C(C)N)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of 45 g of 1-(3-methoxy-phenyl)-ethanone oxime in 675 ml of methanol charged 45 g of Raney Ni. The resultant suspension was agitated at about 28° C. under 3 kg/cm2 anhydrous hydrogen gas pressure for about 4 hours. After completion of the reaction, the reaction mass was filtered through celite and washed with 90 ml of methanol. The filterate was distilled under vacuum at about 55° C. To the residue charged 150 ml of methanolic HCL and distilled completely under vacuum at about 50° C. To the residue charged 100 ml of acetone and stirred at about 15° C. for about one hour. Separated solid was filtered and the solid was washed with 30 ml of acetone. The solid obtained was dried at about 50° C. for about 3 hours.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)(=O)=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(#N)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)OCCCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(Br)cc2)CC1
Temperature: 75 °C

Procedure:
To a stirred solution of 3-(4-bromophenyl)propyl methanesulfonate (4.2 g, 14.33 mmol) in acetonitrile (33.2 ml) was added tert-butyl piperazine-1-carboxylate (3.47 g, 18.62 mmol) and triethylamine (2.60 ml, 18.62 mmol). Reaction mixture heated to 75° C. overnight. The reaction mixture was evaporated to dryness and redissolved in EtOAc (40 mL), and washed with 2:8 saturated brine:water (45 mL). The aqueous was extracted with EtOAc (2×25 mL), organics combined and washed with 2:8 saturated brine:water (2×45 mL) and saturated brine (25 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography using Isco Companion, 50 g silica column, elution gradient 30 to 50% EtOAc in dichloromethane. Pure fractions were evaporated to dryness to afford the sub-title compound as a yellow oil. Yield: 2.4 g
Reaction SMILES: [CH3:1][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C([Li])CCC.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28](OCC)=[O:29])[CH2:24][CH2:23]2)[CH:17]=1.C(O)(=O)C>C1COCC1>[CH2:4]([O:3][P:2]([CH2:1][C:28]([CH:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=2)[CH2:23][CH2:24]1)=[O:29])([O:6][CH2:7][CH3:8])=[O:9])[CH3:5]
Reactant: CCOP(C)(=O)OCC
Reactant: CCOC(=O)C1CCN(c2cc(C)ccn2)CC1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)C1CCN(c2cc(C)ccn2)CC1)OCC
Reaction time: 0.33 h

Procedure:
Diethyl methylphosphonate (1.27 g, 8.36 mmol) was dissolved in anhydrous THF (7 ml), the solution was purged with argon and cooled to −78° C. n-Butyllithium (2M in hexane, 2.67 ml, 5.34 mmol) was added at such a rate that the temperature remained below −65° C. After addition was complete, stirring was continued for 20 minutes, then a solution of ethyl 1-(4-methyl-2-pyridyl)piperidine-4-carboxylate (626 mg, 2.52 mmol) in anhydrous THF (1 ml) was added dropwise so that the temperature remained below −70° C. Stirring was continued overnight while the temperature was allowed to reach room temperature. The mixture was neutralized with glacial acetic acid, concentrated under reduced pressure, water was added and the mixture was extracted with DCM (3×). The combined organic phases were dried (sodium sulfate), and concentrated under reduced pressure to give a brown oil that was used directly in the next step MS (multi-mode) m/z=355.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([NH:28][C:29]([C@@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2C(OC(C)(C)C)=O)=[O:30])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:43])[C:10]=1[O:44][C:45]1[CH:50]=[C:49]([C:51]#[N:52])[CH:48]=[C:47]([Cl:53])[CH:46]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([NH:28][C:29](=[O:30])[C@@H:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:43])[C:10]=1[O:44][C:45]1[CH:50]=[C:49]([C:51]#[N:52])[CH:48]=[C:47]([Cl:53])[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)[C@@H]5CCCN5)ccc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Trifluoroacetic acid (0.25 mL, 3.24 mmol) was added to a suspension of 1,1-dimethylethyl(2S)-2-{[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino}carbonyl]-1H-indol-5-yl)amino]carbonyl}-1-pyrrolidinecarboxylate (0.013 g, 0.020 mmol) in dichloromethane (1 mL). The resulting solution was stirred at RT for 1 h. The solvent was evaporated to give the title compound (0.013 g, 98%) an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.67 (s, 1H), 10.38 (s, 1H), 9.24 (s, 1H), 9.02 (s, 1H), 8.66 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.46-7.55 (m, 2H), 7.36-7.44 (m, 1H), 7.28 (dd, 1H), 7.15 (d, 1H), 4.57 (s, 2H), 4.30 (m, 1H), 3.28 (m, 2H), 1.75-2.14 (m, 4H). MS: m/z 566 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][S:38][CH2:39][CH2:40][NH2:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:41][CH2:40][CH2:39][S:38][CH3:37])=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CSCCN
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCSC)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-(methylthio)-ethylamine.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[CH:28]=[N:29][C:30]2[N:31]([N:33]=[C:34]([SH:36])[N:35]=2)[CH:32]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:36][C:34]3[N:35]=[C:30]4[N:29]=[CH:28][C:27]([CH3:26])=[CH:32][N:31]4[N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cc1cnc2nc(S)nn2c1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4ncc(C)cn4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.52-1.69 (m, 8H) 2.22 (m, 2H) 2.30 (s, 3H) 2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.62 (m, 1H) 2.73 (d, J=17.6 Hz, 1H) 2.98 (d, J=17.9 Hz, 1H) 3.81 (s, 3H) 7.06 (d, J=8.2 Hz, 1H) 7.24 (dd, J=8.5, 1.9 Hz, 1H) 7.30 (d, J=1.9 Hz, 1H) 8.55 (d, J=1.1 Hz, 1H) 8.67 (d, J=2.2 Hz, 1H). MS (APCI) calcd for C25H27ClN4O4S: 515.03; found M=515.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[C:16](OC)([CH3:18])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:16]1([CH3:18])[O:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[O:1]1
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)OC(C)(C)O2
Yield: 48.5 %

Procedure:
Ethyl 3,4-dihydroxybenzoate (910.9 mg, 5 mmol) was combined with 2,2-dimethoxypropane (1.23 mL, 10 mmol) and a catalytic amount of p-toluene sulfonic acid in toluene. The mixture was heated to reflux using a Dean-Stark trap for 20 hours. After solvent removal under reduced pressure, the crude was dissolved in ethyl acetate and washed successively with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic layer was dried over anhydrous sodium sulfate. Purification by chromatography on silica gel using a gradient hexane:ethyl acetate, 90:10 to 75:25, afforded a white powder (539.1 mg, 49%). 1H NMR (CDCl3): 1.36 (t, 3H, J=7.2 Hz), 1.69 (s, 6H), 4.32 (q, 2H, J=7.1 Hz, J=14.2 Hz), 6.74 (d, 1H, d, J=8.2 Hz), 7.38 (d, Ih, J=1.7 Hz), 7.61 (dd, 1H5 J=1.8 Hz, J=8.3 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Br[C:12]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([CH2:21][C:13]2[CH:12]=[CH:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=2)[CH:3]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cnn(Cc2ccc(C(=O)O)cc2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl pyrazole-4-carboxylate (500 mg, 3.57 mmol) and bromo-para-toluic acid (767 mg, 3.57 mmol) in acetone (10 ml) was added potassium carbonate (2.465 g, 17.84 mmol). The suspension was stirred at 50° C. overnight. Water was added to the reaction, and the aqueous phase was washed with ethyl acetate. The pH of the aqueous phase was acidified with 1M hydrochloric acid, and the product was extracted with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (method G) Rt=1.642 min; UPLC (method F) Rt=0.69 min, [M+H]+275.3 [M−H]− 273.3.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][CH2:64]SC)[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].S(Cl)([Cl:70])(=O)=O>ClCCl>[CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][CH2:64][Cl:70])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCSC)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCCl)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Temperature: 25 °C

Procedure:
The compound of Example 8A is dissolved in dichloromethane; sulfuryl chloride (1.1 eq) is added, and the mixture is stirred at ambient temperature until starting material is consumed. The reaction is quenched by the addition of aqeous sodium bicarbonate; the organic layer is removed, and the aqueous phase is re-extracted with dichloromethane. The combined organic phases are dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Yield: 67.3 %

Procedure:
4-(3-Methyl-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (2 g, Example 36a), iron powder (1.74 g), ammonium chloride (1.67 g), ethanol (50 ml) and water (50 ml) were refluxed together under nitrogen for 2 h. The mixture was cooled and the iron was filtered off. Water (200 ml) was added to the residue and the product extracted into ethyl acetate (3×200 ml), dried (MgSO4), and concentrated to give the subtitle compound (1.22 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]([CH2:24][NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].N#N.[H][H]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]([CH2:24][NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of ((S)-5-benzyloxycarbonylamino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (680 mg, 1.27 mmol) in EtOH (20 mL) under an inert atmosphere of N2 is treated with activated palladium on charcoal (10%). The reaction mixture is then placed under a positive pressure of hydrogen and stirred at RT. After 3 h, the mixture is purged with N2 and the catalyst is removed by filtration through Celite® (filter material). The filtrate is concentrated in vacuo and the resulting colourless oil is dissolved in MeOH (10 mL) and allowed to stand at RT overnight. The cream precipitate which forms is removed by filtration and the solution is concentrated in vacuo. The resulting crude product is purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% NH3) to afford the title compound. [M+H]+ 402.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH3:26])[C:19]=3[CH3:27])[CH2:13][O:12][CH2:11]2)=[C:5]([CH3:28])[C:4]=1[CH3:29].[NH2:30][C:31]1[S:32][CH2:33][CH2:34][N:35]=1.CCO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:35]3[CH2:34][CH2:33][S:32][C:31]3=[N:30][C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH3:26])[C:19]=4[CH3:27])[CH2:13][O:12][CH2:11][C:10]2=3)=[C:5]([CH3:28])[C:4]=1[CH3:29]
Reactant: NC1=NCCS1
Reactant: COc1ccc(C=C2COCC(=Cc3ccc(OC)c(C)c3C)C2=O)c(C)c1C
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(C=C2COCC3=C2N=C2SCCN2C3c2ccc(OC)c(C)c2C)c(C)c1C
Yield: 74.5 %

Procedure:
A stirred solution of tetrahydro-3,5-bis[(4-methoxy-2,3-dimethylphenyl)methylene]-4H-pyran-4-one (3.0 g, 7.6 mmole) and 2-amino-2-thiazoline (1.0 g, 9.7 mmole) in 75 ml of CHCl3 is heated at reflux temperature for 72 hours. After cooling, the solution is filtered to remove a small amount of insoluble material. The solvent is evaporated to give an oily residue. Trituration with warm EtOH yields 2.7 g of a yellow solid, m.p. 226°-228° d. Crystallization from 15 ml of DMF gives 2.3 g (63%) of cream colored product, m.p. 235°-237°.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>CC(C)=O>[CH3:1][N:2]([CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: O=S1(=O)CCCO1
Reactant: CNC(C)(C)C
Solvent: CC(C)=O
Product: CN(CCCS(=O)(=O)O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-methyl-tert-butylamine (2.0 g, 22.9 mmol) in acetone (25 mL) was slowly added 1,3-propane sultone (2.72 g, 21.8 mmol). The mixture was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended in 80% Acetone/EtOH. The suspension was stirred at reflux for 30 seconds. The solid product was collected by filtration, and dried in a vacuum oven (50° C.), to afford compound EN (2.9 g, 65%). 1H NMR (DMSO, 500 MHz) δ ppm 9.40 (s (broad), 1H), 3.45 (m, 1H), 2.85 (m, 1H), 2.59 (m, 5H), 1.99 (m, 2H), 1.28 (s, 9H). 13C NMR (DMSO, 125 MHz) δ ppm 63.23, 51.12, 49.73, 34.79, 25.50, 21.72. ES-MS 208 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2.[OH-].[Na+].[I:19]I>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4]([I:19])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1I
Reaction time: 1 h

Procedure:
Combine 4,6-dichloro-indole-2-carboxylic acid, ethyl ester (5.2 g, 20.0 mmol) and sodium hydroxide (0.80 g, 20 mmol) in ethanol (250 mL). Add iodine (5.1 g, 20.0 mmol) as a solution in ethanol (100 mL). After 1 hour, concentrate the reaction mixture in vacuo to obtain a residue. Dissolve the residue in ethyl acetate and extract with 1M hydrochloric acid solution and then with saturated sodium chloride solution. Dry the organic layer over magnesium sulfate and evaporate in vacuo. Chromatograph on silica gel eluting with 25% ethyl acetate/hexane. Combine the product containing fractions and evaporate in vacuo. Recrystallize form ethyl acetate/hexane to give the title compound as a solid; mp: 218°-220° C. Elem. Anal. calculated for C11H8Cl2INO2 : C, 34.41; H, 2.10; N, 3.65. Found: C, 34.67; H, 2.09; N, 3.68.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH2:15]1COCC1>CO.S(=O)(=O)(O)O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)C1CCOc2cc(F)ccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1CCOc2cc(F)ccc21
Temperature: 55 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
7-Fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid (346 mg, 1.76 mmol) was diluted with (THF) 2 mL, methanol (2 mL) and 4 drops of sulfuric acid. The reaction was heated at 55° C. and stirred for 12 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (366 mg, 98.7% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:19]1([N:11]2[C:12]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:18]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ncccc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ncccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of [(S)-1-(1-phenyl-1H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tert-butyl ester (910 mg, 2.69 mmol) in DCM (5 mL) was added TFA (15 mL) and the mixture stirred at RT for 15 min. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a brown solid (340 mg, 53%). 1H NMR (CDCl3, 400 MHz): δ 8.55 (1H, dd, J=4.78, 1.56 Hz), 7.65-7.53 (3H, m), 7.45-7.37 (3H, m), 7.15 (1H, dd, J=8.04, 4.78 Hz), 4.18 (1H, q, J=6.71 Hz), 3.49 (2H, s), 1.48 (3H, d, J=6.71 Hz).