Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]I>[I:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1cc(I)ccn1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Ic1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Yield: 61 %

Procedure:
A mixture of 2-amino-4-iodopyridine (2.60 g, 11.8 mmol), copper (I) iodide (115 mg, 0.60 mmol), 1,10-phenanthroline monohydrate (120 mg, 0.60 mmol) and benzonitrile (33 mL) was heated in a 100 mL 4-necked flask to 130° C. During 23 h a gentle flow of O2/N2 (5:95) was bubbled through the reaction mixture (99% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (10 mL) and dried to yield crude 7-iodo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (2.31 g, 61%) as a green solid with 100% purity (HPLC area-%, HPLC method see below).
Reaction SMILES: C1(C)C=CC(S([N:10]=[N+:11]=[N-])(=O)=O)=CC=1.[CH3:14][O:15][C:16](=[O:24])[CH2:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22].C(N(CC)CC)C>C(#N)C>[CH3:14][O:15][C:16](=[O:24])[C:17](=[N+:10]=[N-:11])[C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: C=CCCC(=O)CC(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCCC(=O)C(=[N+]=[N-])C(=O)OC
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of p-toluenesulfonyl azide (592 mg; 3 mmol) in 1 ml of acetonitrile was added at room temperature to a solution of 3-oxo-6-heptenoic acid methyl ester (468 mg; 3 mmol) and triethylamine (306 mg; 3 mmol) in 5 ml of acetonitrile. The mixture was stirred for about 2 hours and the solvent was distilled off under a reduced pressure and the product was dissolved in 50 ml of ether. The solution was washed with a 5% aqueous solution of potassium hydroxide until no color remained in the aqueous phase and was further washed with a saturated aqueous solution of sodium chloride. The ether solution was dried over anhydrous magnesium sulfate and was filtered and condensed under a reduced pressure to obtain 530 mg of 2-diazo-3-oxo-6-heptenoic acid methyl ester as a yellow oily product. The crude product can be purified by distillation under reduced pressure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.N1CCCC1.[C:14]([NH:21][C@@H:22]([C:24]([OH:26])=O)[CH3:23])([O:16]C(C)(C)C)=O.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH2:43]([N:45]1[CH:49]=[C:48]([C:50]2[N:55]=[C:54]3[C:56](C(O)=O)=[CH:57][N:58](COCC[Si](C)(C)C)[C:53]3=[N:52][CH:51]=2)[CH:47]=[N:46]1)[CH3:44].C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)C(O)=O>>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:24](=[O:26])[C@H:22]([NH:21][C:14]([C:56]2[C:54]3[C:53](=[N:52][CH:51]=[C:50]([C:48]4[CH:47]=[N:46][N:45]([CH2:43][CH3:44])[CH:49]=4)[N:55]=3)[NH:58][CH:57]=2)=[O:16])[CH3:23])[CH2:2][CH2:3]1)#[N:8]
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CC1CCNCC1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Solvent: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CCC(C#N)CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting piperidine-4-carbonitrile for pyrrolidine, Boc-D-alanine for Boc-D-tert-leucine, and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. Trifluoroacetic acid was used in place of hydrochloric acid for all N-Boc deprotection steps. MS: (M+H)+=421.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=[CH:24][C:18]=4[O:17][C:16]=3[C:15]([O:28][CH3:29])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.O.NN>[Ni].CO.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=4[O:17][C:16]=3[C:15]([O:28][CH3:29])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccc(OC)c3oc4ccc([N+](=O)[O-])cc4c23)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(OC)c3oc4ccc(N)cc4c23)cc1
Yield: 69.6 %

Procedure:
N1-(4-methoxyphenyl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (140 mg) (from step 1) was reduced using raney nickel (100 mg) in methanol (40 ml) and DMF (10 ml) in the presence of hydrazine hydrate (1.0 ml) under gentle reflux for 1 h. The reaction mixture was fliterd through celite and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which was filtered dried to give the product as white solid (90 mg).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f52) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([Cl:11])=[N:9][OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:14][S:15]([O:10][N:9]=[C:8]([Cl:11])[C:7]1[CH:12]=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ccc(C(Cl)=NO)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C(Cl)=NOS(C)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Into a solution of 6.7 g of 4-isopropylbenzohydroximoyl chloride in 175 ml of benzene was added in one portion 5.2 g of triethylamine. To this solution was added dropwise during 15 minutes (mildly exothermic reaction) 4.0 g of methanesulfonyl chloride. The mixture was stirred for 30 minutes and filtered. The filtrate was concentrated and the residue recrystallized twice from ethanol to give 8.1 g of N-(methanesulfonyloxy)-4-isopropylbenzimidoyl chloride, m.p. 79.5°-82°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][CH:2]([F:33])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[N:14]([N:18]=[C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=4[CH:23]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[F:33][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[N:14]([N:18]=[C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]4[CH2:26][CH2:27][N:28]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:29][CH2:30][C:24]=4[CH:23]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C(=O)CCl
Reactant: Fc1ccc(OCC(F)F)c(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(F)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-5-fluoro-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-fluoro-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.097 g, 0.210 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.033 mL, 0.321 mmol) in a manner analogous to Example 313 to give product (0.045 g, 39%). MP=218° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.53 (s, 1H), 8.78 (d, 1H), 7.62 (m, 2H), 7.40 (m, 2H), 7.29 (m, 2H), 7.00 (m, 2H), 6.23 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 2.80 (br m, 7H), 2.60 (m, 4H). MS=539 (MH)+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17]CC)=[O:16])=[CH:4][N:3]=1.[OH-].[Na+].Cl>CCO.O>[OH:1][C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:10])([F:11])[F:12])[C:5]([C:15]([OH:17])=[O:16])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(O)nc1C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc(O)nc1C(F)(F)C(F)(F)F
Yield: 98.4 %

Procedure:
A solution of ethyl 2-hydroxy-4-pentafluoroethylpyrimidine-5-carboxylate (4.0 g, 13 mmol) and NaOH (1.60 g, 39 mmol) in EtOH (20 mL) and H2O (45 mL) was heated at reflux for 1 h. The solution was cooled and acidified (concentrated HCl). The resulting solid was filtered and dried to provide 2-hydroxy-4-pentafluoroethylpyrimidine-5-carboxylic acid (3.3 g, 98% yield); 1H NMR (DMSO-d6) δ 9.90 (bs, 1H), 8.43 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:27][C:28]1[O:32][C:31]([CH3:33])=[N:30][CH:29]=1>CN(C)C=O>[CH3:33][C:31]1[O:32][C:28]([CH2:27][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:29][N:30]=1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Reactant: Cc1ncc(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 26 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole in 282 parts of N,N-dimethylformamide there were added 4.8 parts of a dispersion of sodium hydride in mineral oil (50%) under a nitrogen atmosphere. After stirring for 1 hour, there was added portionwise a solution of 15 parts of 5-(bromomethyl)-2-methyloxazole in 47 parts of N,N-dimethylformamide, while cooling in an ice-bath (<20° C.). The whole was stirred for 18 hours and allowed to warm to room temperature. The oily layer was separated and discarded. The N,N-dimethylformamide layer was poured into water and the whole was extracted with 4-methyl-2-pentanone (3×). The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was successively crystallized from 2,2'-oxybispropane and acetonitrile, yielding 14.31 parts (42.0%) of 1-[(2-methyl-5-oxazolyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole; mp. 108.6° C. (comp. 1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[NH:7][C:8](=[O:10])[CH3:9].[CH3:13][NH:14][CH3:15].[CH2:16]=O>CN(C)C=O>[CH3:13][N:14]([CH2:16][C:3]1[C:2]([OH:1])=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[C:5]([CH3:12])[CH:4]=1)[CH3:15]
Reactant: CC(=O)Nc1cc(O)ccc1C
Reactant: CNC
Reactant: C=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(O)c(CN(C)C)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
14.86 g (90.1 mmol) of 5'-hydroxy-2'-methylacetanilide was dissolved in 50 ml of N,N-dimethylformamide. 32.9 g of 40% (w/w) aqueous solution of dimethylamine and 14.6 g of 37% (w/w) aqueous solution of formalin were added to the solution, and the mixture was stirred for 24 hours at room temperature. After the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. 17.1 mg (yield: 91.2%) of the title compound was obtained by washing this crude product with n-hexane and collecting crystals by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CN1CCC[C@H]1CO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and (2S)-2-hydroxymethyl-1-methylpyrrolidine following General Procedure J.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.F[B-](F)(F)F.[F:13][S:14]([F:26])([F:25])([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([N+]#N)=[CH:17][CH:16]=1>>[F:13][S:14]([F:23])([F:24])([F:25])([F:26])[C:15]1[CH:16]=[CH:17][C:18]([N:5]=[N+:6]=[N-:7])=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Product: [N-]=[N+]=Nc1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
(Sheppard, J. Am. Chem. Soc. 1962, 84, 3064-3072) Trimethylsilyl azide (6.5 mg, 0.056 mmol) was added to a solution of 1 (10.2 mg, 0.0321 mmol) in [BMIM][BF4] (65.0 mg). After stirring for 5 min, the mixture was extracted with hexane (0.5 mL×3) and the combined extracts was evaporated to give pure 25a as a colorless oil (6.8 mg, 86%): IR (ATR): {tilde over (v)}=2124, 2099, 1586, 1501, 1287, 843 cm−1. MS (GC, EI): m/z=245 [M+], 219 [M+-CN], 200 [M+-CFN], 111. 1H NMR (500 MHz, CDCl3): δ=7.74 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=150.3 (C), 143.3 (C), 127.7 (2CH), 118.9 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.4 (quint, J=150 Hz, 1 F), 63.5 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:20]([N:15]1[C:16](=[O:19])[C:17]2[NH:18][C:10]([C:5]34[CH2:8][CH2:9][C:2]([NH:1][CH2:32][C:28]5[S:27][CH:31]=[CH:30][CH:29]=5)([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)=[N:11][C:12]=2[N:13]([CH2:24][CH2:25][CH3:26])[C:14]1=[O:23])[CH2:21][CH3:22]
Reactant: O=Cc1cccs1
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(C34CCC(NCc5cccs5)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 24 h

Procedure:
To a solution of 100 mg of 8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 20) (0.28 mmol) and 37 mg of thiophene-2-carboxaldehyde (0.33 mmol) in CH2Cl2 (5 ml) was added 5 drops of glacial acetic acid and 100 mg of sodium triacetoxyborohydride (0.47 mmol). Complete conversion occurs over 24 h at rt. The reaction mixture was quenched with 2 ml of ethanol and 2 ml of 2N HCl and then concentrated in vacuo to afford a colorless oil which was purified from anhydrous acetonitrile to afford 50.8 mg (40%) as a white solid (MH+=456.29). The following compounds were prepared in an analogous manner:
Reaction SMILES: [BrH:1].Br.[NH2:3][C:4]1[C:9](Cl)=[C:8]([NH2:11])[C:7](Cl)=[C:6](Cl)[N:5]=1.[H][H]>C(O)C.[Pt]=O>[BrH:1].[BrH:1].[NH2:11][CH:8]1[CH2:7][CH2:6][NH:5][C:4](=[NH:3])[CH2:9]1
Reactant: Nc1nc(Cl)c(Cl)c(N)c1Cl
Reactant: [H][H]
Agent: O=[Pt]
Agent: Br
Solvent: CCO
Product: N=C1CC(N)CCN1

Procedure:
2,4-Diamino-3,5,6-trichloropyridine dihydrobromide (1.1 g) and platinum oxide (520 mg) in ethanol (50 mL) were shaken on a Parr hydrogenation apparatus at 55 psi of hydrogen for 48 hours. The contents were filtered and the filtrate was concentrated in vacuo leaving a waxy solid. The solid was triturated with ether/EtOH to give 4-amino-2-iminopiperidine dihydrobromide as a white solid. The analysis of the product was found to be consistent with the proposed structure. MH+=114; 1H NMR (D2 O): δ3.80-3.60 (m, 1H); 3.55-3.25 (m, 1H); 3.08-2.95 (m, 1H); 2.76-2.62 (m, 1H); 2.25-2.13 (m, 1H); 1.95-1.80 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]3[CH:13]=[CH:14][CH:15]=[C:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)C.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CC(=O)OCC>[CH3:16][O:18][C:19](=[O:22])[CH2:20][N:12]1[CH2:11][CH2:10][N:9]2[CH:13]=[CH:14][CH:15]=[C:8]2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2NCCn3cccc32)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COC(=O)CN1CCn2cccc2C1c1ccccc1
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
A mixture of (1.0 g, 5.0 mmol) of 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine, 2-bromoacetic acid ethyl ester (587 μl, 5.3 mmol) and potassium carbonate (1.74 g, 12.6 mmol) in acetonitrile (20 ml) was heated for 2 h under reflux. Water (10 ml) and EA (20 ml) were then added, stirring was carried out for 15 min, and the phases were separated. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 1.38 g of 2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)acetic acid methyl ester were obtained as residue and used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:11]([N:13]([CH2:15][CH2:16][CH2:17][P:18](=[O:21])([OH:20])[OH:19])[OH:14])=[O:12].[OH-].[Na+]>CC(C)=O.O>[C:1]([O:14][N:13]([CH2:15][CH2:16][CH2:17][P:18](=[O:20])([OH:19])[OH:21])[CH:11]=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=CN(O)CCCP(=O)(O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=CN(CCCP(=O)(O)O)OC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
A solution of benzoyl chloride (700 mg) in dry acetone (6 ml) was added dropwise to a solution of sodium salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (820 mg) in a mixture of water (15 ml) and acetone (15 ml) under ice-cooling, while stirring. During this period, pH of the mixture was kept at around 7.5-7.7 with 1 N aqueous sodium hydroxide solution. The stirring was continued at the same temperature for 10 minutes and then acetone was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 3.5 with 1N hydrochloric acid and ether (40 ml) was added thereto. After removal of the precipitated impurities, the aqueous layer was adjusted to pH 1.6 with 1N hydrochloric acid and extracted three times with ethyl acetate (50 ml, 20 ml×2). The combined ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to give crystals, which were washed with ether to give crystalline 3-(N-benzoyloxy-N-formylamino)propylphosphonic acid (620 mg). Mp 149°-153° C. (dec.).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([F:14])[C:10]([Cl:13])=[N:11][CH:12]=1.CN([CH:18]=[O:19])C.CCOC(C)=O>CCOCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([CH:18]=[O:19])=[CH:8][C:9]=1[F:14]
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=Cc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyl lithium (2.5 M in hexane, 2.5 mL, 6.3 mmol) was added to 5-bromo-2-chloro-3-fluoro-pyridine (1 g, 4.75 mmol) in 10 mL of ether at −78° C. After 10 minutes, DMF (5 mL) was added and the mixture was warmed to room temperature over 1 h. The mixture was poured into 20 mL of EtOAc and the mixture was washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate and concentrated to afford the crude 53a (0.92 g) as a brown oil: LC-MS160.0 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1F.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: N#Cc1ccc(C2OCCCO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2OCCCO2)c(Sc2ccccc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (207 mg, 1 mmol) and thiophenol (100 mg, 0.9 mmol; 1.1 eq.) were initially charged in DMF (3 ml). Potassium carbonate (314 mg, 2.27 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at 100° C. for 4 h. LC/MS control then showed complete conversion. The reaction mixture was purified directly by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (238 mg, 80% of theory).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C1COCC1.[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:20]([C:22]3[C:23]([O:39][CH3:40])=[C:24]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)=[O:37])[CH:31]=4)[C:25]([CH3:29])=[C:26]([Cl:28])[CH:27]=3)[CH3:21])[N:18]=[CH:19][C:12]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[NH2:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]2[N:17]([CH:20]([C:22]3[C:23]([O:39][CH3:40])=[C:24]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:4][CH2:3][CH2:1][OH:2])=[O:37])[CH:31]=4)[C:25]([CH3:29])=[C:26]([Cl:28])[CH:27]=3)[CH3:21])[N:18]=[CH:19][C:12]=12
Reactant: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)O)c1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)NCCO)c1
Reaction time: 1 h

Procedure:
Ethanolamine (2.0 M) in THF (0.14 mL, 0.28 mmol) was added to a solution of 4-{3-[1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (from Example 38, Step 2) (18.6 mg, 0.042 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature followed by adding triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 hour, then quenched with water. The mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C23H25ClN7O3 (M+H)+: m/z=482.2; Found: 482.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ncccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 2-chloropyridin-3-ol (16.3 g, 125 mmol) and K2CO3 (24.3 g, 176 mmol) in acetone (150 ml) was added dropwise (bromomethyl)benzene (17.9 ml, 151 mmol). The mixture was stirred overnight at 50° C. and then concentrated to dryness. Water (100 ml) was added and the mixture extracted with CH2Cl2. The organics were dried over Na2SO4, and concentrated to a crude residue that was dissolved in 20 ml CH2Cl2. Et2O (250 ml) was added and then the solvent was decanted from the residue. The residue was then purified on a silica gel plug by eluting with 25% EtOAc/Hexanes to give 3-(benzyloxy)-2-chloropyridine (22.3 g, 80% yield) as a solid.