Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:45])[C:7](=[CH2:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:34])[CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24]CC2C=CC=CC=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC>CO>[CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:33])[CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
175 mg of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in the presence of 12 mg of [Ru2Cl4 (S-Binap)2 ].(NEt3) in 30 ml of methanol for 20 hours at room temperature and under 30 bar. The reaction mixture is filtered, concentrated by evaporation and purified by means of FC (hexane/ethyl acetate=1:1). The title compound so obtained (Rf in hexane/ethyl acetate=1:1)=0.15 is deprotected by hydrogenation with 90 mg of 10% Pd/C in 10 ml of methanol at room temperature and under normal pressure to form N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy--5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide.
Reaction SMILES: [CH2:1]([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[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:52]=[C:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[O:54][CH:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[CH2:1]([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[CH:46]=[C:47]([C:51]3[N:52]=[C:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[O:54][CH:55]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3coc(-c4ccccc4)n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3coc(-c4ccccc4)n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 103 from 4'-[(2-n-propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([CH2:14][C:15]#[N:16])=[CH:3]1>C1COCC1.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([CH2:14][C:15]#[N:16])=[CH:3]1
Reactant: Cn1cc(CC#N)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1cc(CC#N)c2cc(N)ccc21
Reaction time: 6 h
Yield: 94.8 %

Procedure:
To a solution of 8.9 g (0.041 mole) of 1-methyl-5-nitroindole-3-acetonitrile in 600 ml of THF was added 3 g of 10% Pd/C. The mixture was hydrogenated in a Parr apparatus at 50 psi for 6 hours. The resulting mixture was filtered through celite treated with charcoal and filtered again through celite. The solvent was removed in vacuo leaving 7.2 g of the tan solid. This material was used directly without purification for the next step.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:8]1[C:20]([O:21]C)=[CH:19][C:18]2[N:17]([CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:16]3[CH:15]=[CH:14][C:13]4[C:29](=[O:32])[CH2:30][CH2:31][C:12]=4[C:11]=3[C:10]=2[CH:9]=1)(=[O:7])[CH3:6].C(Cl)Cl.CO.Cl>C(Cl)Cl.O1CCOCC1>[C:5]([C:8]1[C:20]([OH:21])=[CH:19][C:18]2[N:17]([CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:16]3[CH:15]=[CH:14][C:13]4[C:29](=[O:32])[CH2:30][CH2:31][C:12]=4[C:11]=3[C:10]=2[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1cc2c(cc1C(C)=O)c1c3c(ccc1n2CCCN(C)C)C(=O)CC3
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1cc2c3c4c(ccc3n(CCCN(C)C)c2cc1O)C(=O)CC4
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
A 0.5 M solution of BBr3 (16.5 mL, 5 eq.) was added dropwise under argon to a solution of compound 38 (0.658 g, 1.74 mmol) in CH2Cl2 (100 mL) cooled to −40° C. The mixture was kept for 10 min; then a cooling bath was removed and the mixture was heated to room temperature and kept for 1-2 h (TLC monitoring, eluent: CHCl3/NH3-MeOH, 9:1). The resulting mixture was poured in a mixture of aqueous NaHCO3 solution and CH2Cl2. The organic layer was separated; the aqueous one was extracted with CH2Cl2, dried over Na2SO4, evaporated, and dissolved in a mixture: CHCl3-MeOH-water, 40:9:1. The product was purified in a silica gel column with the use of the latter mixture as an eluent. Yield of Example 4: 0.258 g (41%). For the preparation of hydrochloride, the product isolated was dissolved in a mixture: CH2Cl2-MeOH; a solution of HCl in dioxane was added. The resulting mixture was evaporated to dryness; the residue was washed with ether.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1.[CH:32]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>>[CH:32]1([CH2:35][S:36]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]3[C:5]([C:15]4[N:16]=[C:17]5[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:18]5=[N:19][CH:20]=4)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:10]2)(=[O:38])=[O:37])[CH2:34][CH2:33]1
Reactant: O=S(=O)(Cl)CC1CC1
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCNC2)n1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCN(S(=O)(=O)CC3CC3)C2)n1

Procedure:
(1-Cyclopropylmethanesulfonyl-piperidin-3-yl)-{6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from {6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-piperidin-3-yl-amine, and cyclopropyl methanesulfonyl chloride, using 3 equivalents of DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:26]3[CH:27]=[C:28]4[O:33][CH2:32][O:31][C:29]4=[CH:30][C:25]=3[CH2:24][CH:23]([CH3:34])[N:22]([C:35](=[O:38])[CH2:36]Cl)[N:21]=2)=[CH:16][CH:15]=1)([O-])=O>C(O)C>[NH2:11][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:26]3[CH:27]=[C:28]4[O:33][CH2:32][O:31][C:29]4=[CH:30][C:25]=3[CH2:24][CH:23]([CH3:34])[N:22]([C:35](=[O:38])[CH2:36][NH:6][CH3:4])[N:21]=2)=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)CCl)OCO3
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNCC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Yield: 53.5 %

Procedure:
1.03 g (15.3 mmol) of methylamine hydrochloride and 2.64 ml (18.3 mmol) of triethylamine were added to a suspension containing 1.23 g (3.06 mmol) of 1-(4-nitrophenyl)-3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 140 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was dissolved in 30 ml of chloroform, washed with 20 ml of 4% NaOH solution, then 2×20 ml of water, dried and evaporated under reduced pressure. The residue was reduced according to the process of Example 16 and the product obtained was purified by column chromatography (adsorbent: Kieselgel 60, eluent: methanol--benzene 4:1). The crude product obtained was triturated with 5 ml of ethyl acetate at 25° C. to obtain 0.60 g (53.6%) of the aimed product, m.p. 198°-200° C. (weak decomp.).
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.ClC1C=CC(OCC2C3C=NC(C(OCC)=O)=CC=3N(CC)C=2)=CC=1.[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([OH:81])=[C:62]([CH:80]=1)[CH2:63][C:64]1[C:68]2[CH:69]=[N:70][C:71]([C:73]([O:75]CC)=O)=[CH:72][C:67]=2[N:66]([CH2:78][CH3:79])[CH:65]=1>>[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([OH:81])=[C:62]([CH:80]=1)[CH2:63][C:64]1[C:68]2[CH:69]=[N:70][C:71]([C:73]([NH:21][OH:22])=[O:75])=[CH:72][C:67]=2[N:66]([CH2:78][CH3:79])[CH:65]=1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOC(=O)c1cc2c(cn1)c(Cc1cc(Cl)ccc1O)cn2CC
Agent: CCOC(=O)c1cc2c(cn1)c(COc1ccc(Cl)cc1)cn2CC
Product: CCn1cc(Cc2cc(Cl)ccc2O)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(3-chloro-2-hydroxybenzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 4-chlorophenol using a methods similar to that set forth in Example 55. (b) 3-(5-Chloro-2-hydroxybenzyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from the mixture of ethyl 3-(4-chloro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(5-chloro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([O:22][CH3:23])(=[O:21])[C@H:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[OH:15].CI>O1CCCC1.C(O)(=O)C.CCOCC>[OH:15][C@@H:14]([C@H:16]([CH3:1])[C:17]([O:19][CH3:20])=[O:18])[C:13]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C[C@H](O)C(=O)OC
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)[C@@H](C)[C@H](O)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a −78° C. solution of 9.09 mL (65 mmol) of diisopropylamine in 100 mL of tetrahydrofuran was added dropwise 40.5 mL (65 mmol) of 1.6 M n-butyl lithium in hexanes. The solution was allowed to warm to 0° C. briefly before being cooled to −78° C. To the solution was added 4.09 mL (30.9 mmol) of dimethyl (S)-(−)-malate dropwise and the resulting solution was allowed to warm to room temperature. After 30 min at room temperature, it was cooled to −78° C. before 2.3 mL (37.1 mmol) of methyl iodide was added dropwise. The solution was allowed to warm to room temperature, and was stirred for 18 h. It was then poured onto a mixture of ether, ice water, and 9.27 mL of acetic acid. The resulting mixture was extracted with ether, and the extracts were combined, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to afford 1.04 g (5.9 mmol) of dimethyl (2S,3S)-2-hydroxy-3-methylbutanedioate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CC([O-])(C)C.[Na+]>CC(O)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=3[CH:18]=2)[CH2:22][CH2:21]1
Reactant: C[Si](C)(C)CCOCn1cnc2ccc(Br)cc21
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc3ncn(COCC[Si](C)(C)C)c3c2)CC1
Temperature: 100 °C
Yield: 73 %

Procedure:
(Buchwald coupling): In a microwave reaction vial a suspension of 6-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (500 mg, 1.53 mmol), 1-methyl-piperazine (0.203 mL, 1.83 mmol) Pd2(dba)3 (0) (14 mg, 0.015 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (36 mg, 0.076 mmol) and NaOtBu (206 mg, 2.14 mmol) in 2-methyl-propan-2-ol (1.5 mL) was degassed with nitrogen. The reaction was heated in a microwave reaction at 100° C. for 1 hour. The mixture was diluted with H2O, acidified by the addition of 2M aqueous HCl, stirred with EtOAc and then filtered. The EtOAc layer was then extracted with H2O (×3). The combined aqueous fractions were neutralized with saturated NaHCO3 solution and then extracted with CHCl3/iPrOH (2:1) (×3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The product was purified by SiO2 chromatography providing the title compound (387 mg).
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[CH3:36][CH:37]1[O:42][CH:41]([CH3:43])[CH2:40][NH:39][CH2:38]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:39]5[CH2:38][CH:37]([CH3:36])[O:42][CH:41]([CH3:43])[CH2:40]5)[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: CC1CNCC(C)O1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CC(C)OC(C)C1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2,6-dimethylmorpholino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and 2,6-dimethylmorpholine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[OH:21][C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([N:25]2[CH2:26][CH2:27][C:22]([OH:21])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:24]2)=[O:20])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: OC1(c2ccccc2)CCNCC1
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with 4-hydroxy-4-phenyl-piperidine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[CH:20]=[N:21][NH:22][C:16]=2[CH2:15]1)=[O:13].[I:23]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20]([I:23])=[N:21][NH:22][C:16]=2[CH2:15]1)=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2cn[nH]c2C1
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(I)n[nH]c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of 6-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (63 mg, 0.191 mmol) in DMF (1 mL) was added N-iodosuccinimide (47 mg, 0.210 mmol). The reaction was allowed to stir for 2 h at rt then poured into ice water (10 mL). The product was extracted with EtOAc three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-50% ethyl acetatehexanes) provided the desired product (48 mg, 55%). MS (ESI) mass calcd. C14H10ClF31N3O, 454.95. m/z found, 455.9 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.27 (br s, 1H), 7.81-7.74 (m, 1H), 7.52-7.43 (m, 2H), 5.13 (d, J=16.7 Hz, 0.6H), 4.82 (d, J=16.7 Hz, 0.6H), 4.47 (d, J=16.0 Hz, 0.4H), 4.37 (d, J=16.0 Hz, 0.4H), 4.27-4.19 (m, 0.4H), 3.95-3.85 (m, 0.4H), 3.45-3.50 (m, 1.2H), 2.62-2.66 (m, 0.8H), 2.51 (m, 0.6H), 2.46-2.37 (m, 0.6H).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:3][C:2]#[CH:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccccc1-c1ccccc1
Temperature: 65 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
To a solution of propargyl bromide (80% solution in toluene, 500 δ 3.36 mmol) in acetone (15 ml) at 23° C. was added 2-phenyl phenol (316 mg, 1.86 mmol) and potassium carbonate (1.05 g, 7.61 mmol). After being stirred in a sealed reaction vial at 65° C. for 14 hours, the reaction was concentrated in vacuo, the residue purified by flash chromatography (ethyl acetate:hexane: 9:1) to afford compound 5 in 95% yield. 1H NMR(CDCl3) δ 2.45-2.55 (m, 1H), 4.60-4.70 (m, 2H), 6.99-7.43 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[C:15]([Cl:34])=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[H-].[Na+].[C:37]([N:41]=[C:42]=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CN(C=O)C>[C:37]([NH:41][C:42](=[O:43])[NH:1][C:2]1[C:3]([C:14]2[C:15]([Cl:34])=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N—[3-(7-amino-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-6-yl)-2,4-dichloro-phenyl]-3-trifluoromethyl-benzamide (700 mg, 1.34 mmol) in dry DMF (10 ml) at 0° C. is added NaH (60% oil suspension, 64 mg, 1.6 mmol) slowly. The reaction mixture is stirred at room temperature for 30 minutes and then to this reaction mixture t-butyl-isocyanate (0.19 ml, 1.6 mmol) is added. The reaction is stirred at room temperature for 5 hours. The reaction mixture is diluted into 100 ml water, extracted with 80 ml ethyl acetate three times. The organic phase is combined and washed with brine, dried over Na2SO4. The crude product is purified by flash silica gel column to give the title compound as light yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:3]1.C(N(CC)CC)C.Cl[C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1>C(#N)C>[NH2:29][C:27]1[N:28]=[C:23]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:9])[CH2:3]2)[CH:24]=[CH:25][C:26]=1[N+:30]([O-:32])=[O:31]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Temperature: 10 °C
Yield: 104.7 %

Procedure:
To a suspension of (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (45.56 g, 208.3 mmol) in anhydrous acetonitrile (200 mL) at 10° C. was added triethylamine (50 mL). The suspension was poured into a 2 L 3-neck flask equipped with a thermometer and a magnetic stirrer. To the original flask was added anhydrous acetonitrile followed by sonication and addition of triethylamine (80 mL). The suspensions were combined and cooled to 10° C. and 6-chloro-3-nitropyridin-2-amine (32.97 g, 190 mmol) was added. The bright yellow solution was stirred under nitrogen while the temperature was increased gradually to 80° C. over 1 h. The reaction mixture was cooled to room temperature. The resulting suspension was filtered and the solids were rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride (500 mL) was added to the residue and the mixture was extracted into ethyl acetate (2×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried for 18 h under high vacuum to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone as a yellow foam (63.51 g). 1H NMR (400 MHz, CD3OD) δ 1.47-1.64 (m, 1H) 1.71-2.07 (m, 7H) 2.68 (tt, 1H) 3.01 (q, 2H) 3.33-3.46 (m, 2H) 3.52 (dt, 1H) 3.60-3.70 (m, 1H) 4.41 (br s, 1H) 4.71 (d, 1H) 6.23 (d, 1H) 8.05 (d, 1H); MS (ES+) (M+H) 320.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[C:9](=[N:19]/[OH:20])/[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[OH:18].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:20]/[N:19]=[C:9](/[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])\[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[OH:18])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(=N\O)c2cc(F)ccc2F)c(O)c1
Product: COc1ccc(/C(=N\OC(C)=O)c2cc(F)ccc2F)c(O)c1
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
A mixture of 40 g of 2',5'-difluoro-2-hydroxy-4-methoxybenzophenone hydrochloride and 230 ml of pyridine is refluxed overnight. The pyridine is evaporated in vacuo. The residue is partitioned between 5% hydrochloric acid and ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and evaporated. The residue was triturated with hexane to give E-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone oxime. A mixture of 35 g of the oxime and 25.6 g of acetic anhydride is placed in an oil bath at 60° C. for 45 min. The reaction mixture is partitioned between ether and sodium bicarbonate solution. The ether extract is dried over anhydrous sodium sulfate and evaporated. Recrystallization of the residue from 95% ethanol gives 30 g of E-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp 110°-111° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[CH3:14].[CH2:15]([N:22]1[C:30]2[C:29](Cl)=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1.O>[CH2:15]([N:22]1[C:30]2[C:29]([O:3][C:4]3[C:9]([CH3:10])=[CH:8][C:7]([C:11](=[O:13])[CH3:12])=[CH:6][C:5]=3[CH3:14])=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1cc(C)c(O)c(C)c1
Reactant: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc(C)c(Oc2nc(Cl)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a stirred solution of NaH (31 mg, 0.78 mmol) in dry NMP (2 mL) was added 1-(4-hydroxy-3,5-dimethylphenyl)ethanone (127 mg, 0.78 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (216 mg, 0.78 mmol) in dry NMP (2.4 mL) and heated at 160° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1-2:1), to give the product as a light yellow solid (111 mg, 35%).