Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1CC#N.[OH-:13].[K+].[CH2:15]([OH:18])[CH2:16]O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:16][C:15]([OH:18])=[O:13]
Reactant: [OH-]
Reactant: OCCO
Reactant: COc1ccc(CC#N)c(Cl)c1
Agent: [K+]
Product: COc1ccc(CC(=O)O)c(Cl)c1

Procedure:
657 g (purity 75%) of 2-chloro-4-methoxyphenylacetonitrile are reacted with 303 g of potassium hydroxide in 1308 ml of ethylene glycol. 430 g of solid are obtained (m.p.: 83-86° C.).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[Cu][C:35]#[N:36]>CN1C(=O)CCC1>[C:35]([C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8])#[N:36]
Reactant: N#C[Cu]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CN1CCCC1=O
Product: Cc1c(C#N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide Example 1 (d), 120 mg, 0.20 mmol) and copper (I) cyanide (66.7 mg, 0.74 mmol) in NMP (2.5 ml) was stirred overnight at 140° C. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was first purified by preparative HPLC and then by flash chromatography eluting with dichloromethane/methanol (10:0.2) to give the title compound as a white solid (24 mg, 24%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([O:34][CH:35]([CH3:37])[CH3:36])[NH2:33]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:27]3[O:29][N:33]=[C:32]([O:34][CH:35]([CH3:37])[CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)OC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: CC(C)Oc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
According to General Method 1, 150 mg (0.362 mmol) of the compound from Example 58A and 62.7 mg (0.398 mmol, purity 75%) of isopropyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were reacted. Yield: 41.6 mg (23% of theory).
Reaction SMILES: [O:1]([C:8]([CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12.C(N(CC)CC)C.C>ClCCl.C(=O)(O)[O-].[Na+]>[O:1]([C:8]([CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([NH:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12)=[O:12])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)C(C(=O)Oc1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
α-(Phenoxycarbonyl)phenylacetyl chloride (0.02 M) in dichloromethane (50 ml.) was added to 7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylic acid (6.56 g., 0.02 M) and triethylamine (6.0 ml.) in dichloromethane (100 ml.). The resulting solution was stirred at room temperature for three hours then the solvent was removed in vacuo, the residue dissolved in water (200 ml.) and washed with ethyl acetate (2×100 ml.). The aqueous solution was covered with ethyl acetate (50 ml.) acidified to pH 1.5 with 1 N hydrochloric acid, filtered, the organic phase was collected and the aqueous phase extracted with more ethyl acetate (50 ml.). The combined extracts were washed with water (2×100 ml.) and saturated sodium chloride (50 ml.) dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo to give an oily residue which was triturated with anhydrous ether to give a pale brown solid (5.0 g.). This solid was dissolved in dilute sodium bicarbonate solution (100 ml.), treated with decolourising charcoal, filtered, acidified to pH 1.5 and the precipitated cephalosporin free acid collected and dried in vacuo.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>CN(C=O)C.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[CH:20]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[CH2:21]
Reactant: COc1cnnc(-c2cccc(C(F)(F)F)c2)c1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd+]
Agent: [CH2-]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(OC)cnnc1-c1cccc(C(F)(F)F)c1
Yield: 41.6 %

Procedure:
4-Bromo-5-methoxy-3-[3-(trifluoromethyl)phenyl]pyridazine (1.0 g, 0.003 mole, Compound No. 57), vinyltributyltin (1.1 g, 0.0034 mole) and trans-benzyl(chloro)bis-(triphenylphosphine)-palladium(II) (20 mg) were heated to 110° C. in DMF (50 mL) under N2 for 4 h. The reaction was then cooled and partitioned between aqueous KF and ethyl acetate. The KF solution was extracted with additional ethyl acetate. The organic layers were washed with brine, dried (MgSO4), filtered through silica gel and then evaporated in vacuo. The crude oil was then chromatographed on a Prep-500 to give 4-ethenyl-5-methoxy-3-[3-(trifluoromethyl)phenyl]pyridazine (0.35 g, 42% yield, Compound No. 55) as a light brown solid.
Reaction SMILES: C1(S[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])[CH:16]=3)[NH:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)CCCC1.BrCC1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](C3C=CC=CC=3OC)[CH:38]=2)[NH:33]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C1(S)CCCC1>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:26])([CH3:27])[CH:9]=[C:8]2[CH2:7][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSC1CCCC1)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: SC1CCCC1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Cyclopentylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 69 mg of potassium carbonate, and 48 μL of cyclopentyl mercaptan reacted to give 7 mg of the title compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[Br:13]N1C(=O)CCC1=O.[OH-].[Na+]>ClCCl>[Br:13][C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[NH:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1Br
Temperature: 25 °C

Procedure:
Ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 7, 300 mg, 1.6 mmol) was dissolved in dry dichloromethane (10 ml), N-bromosuccinimide (285 mg, 1.6 mmol) was added at 0° C. and resulting mixture was stirred at room temperature over night. The mixture was poured into cold sodium hydroxide aqueous solution (2M) (20 ml), extracted with diethyl ether (2×20 ml). The organic phase was then washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (hexanes/ethyl acetate, gradient) to give the desired product as a yellowish solid. (424 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19](OCC)=[O:20])[N:18]=2)[CH:15]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[F:1])=[O:20])[N:18]=2)[CH:15]=1
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1ccccc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 2-fluoroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:30])[C:15]=3[C@H:31]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:32]([O:34][CH3:35])=[O:33])[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:24]=[C:25]([C:43]6[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=6[OH:41])[CH:26]=[CH:27][CH:28]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:30])[C:15]=3[C@H:31]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:32]([O:34][CH3:35])=[O:33])[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccccc1O
Reactant: C=CCC1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6ccccc6O)c5)nn34)cc21
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
A solution of ((2S)-methyl 2-(7-(4-allylchroman-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.430 g, 0.711 mmol), (2-hydroxyphenyl)boronic acid (0.196 g, 1.423 mmol) and 2.0 M aq. Na2CO3 (1.1 ml, 2.1 mmol) in DMF (7 ml) was sparged with nitrogen for 10 min, treated with Pd(Ph3P)4 (0.058 g, 0.050 mmol), then sparged for 5 min. The reaction was stirred for 90 min, then cooled, diluted with water (20 mL) and extracted into Et2O (2×50 mL). The combined extracts were dried (MgSO4), filtered, and concentrated and the residue was purified by biotage (24 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexanes) to afford the desired product (0.360 g, 0.572 mmol, 80% yield) as a pale yellow glassy solid. 1H NMR (500 MHz, CDCl3) δ: 8.07-7.89 (m, 2H), 7.70 (s, 1H), 7.60-7.49 (m, 2H), 7.49-7.36 (m, 2H), 7.34-7.29 (m, 2H), 7.07-6.97 (m, 3H), 6.95-6.90 (m, 1H), 5.96-5.71 (m, 1H), 5.37-5.19 (m, 2H), 5.16-4.97 (m, 2H), 4.39-4.25 (m, 2H), 3.88-3.79 (m, 3H), 3.12-2.88 (m, 1H), 2.72-2.63 (m, 3H), 2.61-2.32 (m, 1H), 2.22-2.08 (m, 1H), 2.02-1.88 (m, 1H), 1.06-0.92 (m, 9H). LCMS (M+H)=618.5.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[C:10]([C:12]1[N:16]([CH3:17])[C:15]([CH2:18][C:19]([O-:21])=[O:20])=[CH:14][CH:13]=1)#N.[Ca].C(C1N(C)C(CC(O)=[O:33])=CC=1)#N>O.O1CCCC1>[CH3:17][N:16]1[C:12]([C:10]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)=[O:33])=[CH:13][CH:14]=[C:15]1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: Cc1ccc(Br)cc1
Reactant: Cn1c(C#N)ccc1CC(=O)[O-]
Reactant: Cn1c(C#N)ccc1CC(=O)O
Agent: [Ca]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Yield: 63 %

Procedure:
To a solution of the Grignard reagent prepared from 0.82 g. (36 mmol) of magnesium and 6.2 g. (36 mmol) of 4-bromotoluene in 15 ml. of anhydrous tetrahydrofuran was added 1.2 g. of solid material which contained about 6.0 mmol of 5-cyano-1-methylpyrrole-2-acetate as the calcium salt and some water which persisted after drying in a vacuum oven. Diphenyl ether (20 g.) was added, and the reaction mixture was heated to remove tetrahydrofuran by distillation until the temperature reached 110° C. The reaction mixture was then heated under reflux for two hours, cooled, and partitioned between ether and dilute aqueous hydrochloric acid. Following a work-up procedure similar to that described for Example 1, there was obtained 130 mg. (13%) of 5-cyano-1-methylpyrrole-2-acetic acid and 970 mg. (yield: 63%, 73% based on unrecovered cyanoacid) of 1-methyl-5-p-toluoylpyrrole-2-acetic acid as brown solids.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH3:10])[N:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[CH2:19][C:20]#[N:21]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19]1[C:20]([NH2:21])=[N:1][C:2]2[N:3]=[CH:4][N:5]=[C:6]([CH3:10])[C:7]=2[CH:8]=1
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: Cc1ncnc(N)c1C=O
Product: Cc1ncnc2nc(N)c(-c3c(Cl)cccc3Cl)cc12

Procedure:
4-Amino-6-methylpyrimidine-5-carboxaldehyde is then condensed with 2,6-dichlorophenylacetonitrile. The crude product is isolated by concentrating the reaction mixture to dryness and partitioning the residue between chloroform and water. Drying and concentration of the organic layer gives a residue which is chromatographed on silica gel. The product is eluted with 1/99 mixture of methanol/chloroform and recrystallized from ethanol to give pure 6-(2,6-dichlorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7-amine, mp 280°-282° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:22][CH2:23]CN=C=NCC.C(O)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[C:11]([OH:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c(O)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1O
Temperature: 25 °C

Procedure:
A mixture of 1.2 g of 4-(t-butoxycarbonylamino)-2-hydroxybenzoic acid, 900 mg of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC·HCl), 550 mg of 4-dimethylaminopyridine, 1 ml of ethanol and 30 ml of dichloromethane was stirred at room temperature. The reaction mixture was treated with dichloromethane as the extracting solvent in an ordinary manner and then purified by the silica gel chromatography (ethyl acetate/hexane) to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:8].[CH:19]1([CH2:22][NH:23][CH2:24][C:25]2[NH:26][C:27](=[O:35])[C:28]3[CH2:34][O:33][CH2:32][CH2:31][C:29]=3[N:30]=2)[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH:19]1([CH2:22][N:23]([CH2:24][C:25]2[NH:26][C:27](=[O:35])[C:28]3[CH2:34][O:33][CH2:32][CH2:31][C:29]=3[N:30]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:8])[CH2:14][CH2:13]2)[CH2:21][CH2:20]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccn1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 41.8 %

Procedure:
To a solution of compound [4-(pyridine-2-carbonyl)-piperidin-1-yl]-acetic acid (178 mg, 0.72 mmol) and 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (169 mg, 0.72 mmol) in DMF (5 mL) and DCM (5 mL) at 0° C. is added DIPEA (0.50 mL, 2.87 mmol) and then HATU (313 mg, 0.82 mmol). The reaction is then stirred at 25° C. for 36 hours. The solvent was removed under vacuum and then solubilized in methanol and filtered. The compound was then purified by reverse phase using sunfire C18 ODB using water acetonitrile and TFA as a buffer to afford the title compound (140 mg). 1H NMR (400 MHz, MeOD) δ: 8.68 (s, 1H), 7.99 (m, 2H), 7.59 (s, 1H), 4.68 (s, 1H), 4.57 (s, 2H), 4.49 (s, 1H), 3.97 (t, J=5.6 Hz, 3H), 3.51 (d, J=7.1 Hz, 1H), 3.40 (s, 2H), 3.36 (s, 2H), 3.35-3.31 (m, 2H), 3.30 (d, J=11.6 Hz, 2H), 2.68-2.58 (m, 2H), 2.37-2.24 (m, 2H), 1.96-1.91 (m, 2H), 1.13-0.97 (m, 1H), 0.62-0.45 (m, 2H), 0.33-0.22 (m, 2H). HRMS calculated for C25H31N5O4=465, 2376. found (ESI, [M+H]+), 465, 2369. LRMS m/z: ES+=466.0 (M+H), retention time 1.04.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1.Br[CH2:13][C:14]([OH:16])=[O:15]>>[CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[C:9]([S:10][CH2:13][C:14]([OH:16])=[O:15])=[N:8][N:7]=[N:6]1
Reactant: O=C(O)CBr
Reactant: CN(C)CCn1nnnc1S
Product: CN(C)CCn1nnnc1SCC(=O)O

Procedure:
2-{1-[2-(dimethylamino)ethyl]-1,2,3,4-tetraazol-5-ylthio}acetic acid was prepared from commercially available 1-(2-dimethylaminoethyl)-5-mercapto-1,2,3,4-tetrazole and bromo acetic acid according to the procedures described in Russian J. Org. Chem. 2000, 761
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][C@@H:21]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:2]([NH:1][C:29]([C:28]2[CH:27]=[CH:26][C:25]([C@@H:21]3[O:22][CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20]3)=[CH:33][CH:32]=2)=[O:30])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)N[C@@H](CO)c3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A mixture of (R)-2-amino-2-(4-fluorophenyl)ethanol (68.6 mg, 0.44 mmol), (S)-4-(4-(tert-butoxycarbonyl)morpholin-2-yl)benzoic acid [CAS 1131220-40-0], (136 mg, 0.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (170 mg, 0.88 mmol), 4-dimethylaminopyridine (54.0 mg, 0.44 mmol) and triethylamine (179 mg, 0.25 ml, 1.77 mmol) in dichloromethane (9 ml) was stirred at room temperature overnight. The reaction was quenched by addition of 1M citric acid solution (5 ml). The organic layer was separated, washed with sodium bicarbonate saturated solution (5 ml), dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, gradient heptane/ethyl acetate), to give a white foam (100 mg, 51%), MS (ISP): 445.4 (100%, [M-tBu+H]+), 389.3 (29%, [M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH:8]=[O:9].[C:17]([O-:20])(O)=O.[Na+].Cl.[CH3:23]O>>[Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH:8]([O:20][CH3:17])[O:9][CH3:23]
Reactant: CCCCc1nc2nc(C=O)c(Br)cc2[nH]1
Reactant: O=C([O-])O
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: CCCCc1nc2nc(C(OC)OC)c(Br)cc2[nH]1
Yield: 92 %

Procedure:
0.57 g (2.02 mmole) of the compound obtained in step 7 was dissolved in 5 ml of 3% HCl/MeOH and heated to reflux for 30 minutes. The reaction solution was cooled and thereto was added saturated NaHCO3 solution. The resultant was extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified with column chromatography (hexane:ethyl acetate=1:1) to obtain 0.61 g of the title compound (yield 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CCOC(C)=O.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:27]#[N:28])=[CH:11][C:10]=1[C:16]([CH3:19])([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1OCc1ccccc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C#N)ccc1OCc1ccccc1
Temperature: 175 °C

Procedure:
1-Benzyloxy-4-bromo-2-tert-butyl-benzene made in example 47B (319 mg, 1 mmol), zinc cyanide (129 mg, 1.1 mmol) and Pd(PPh3)4 (34.5 mg, 0.03 mmol) were mixed in 4 mL of DMF then the mixture was heated to 175 ° C. in a microwave reactor (Emrys Optimizer by Personal Chemistry) for 5 minutes. The mixture was cooled to room temperature, and then water and EtOAc were added. The EtOAc extracts were dried over Na2SO4, concentrated and the resulting residue was purified by flash chromatography (5–10% EtOAc/Hexanes) to give the desired nitrile (64 mg). MS (DCI) m/z 238 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]
Reactant: CC(C)(N)CO
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: CC(C)(CO)NCc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
3,4-Dichlorobenzyl chloride (3.95 g) was added to 2-amino-2-methylpropan-1-ol (17.8 g) and the mixture was stirred at 60° C. under nitrogen for 2 h. Excess amine was removed by distillation under vacuum and the residue was partitioned between saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate (100 ml). The phases were separated, the organic layer was washed with water (4×100 ml) and brine (100 ml), dried (Na2SO4) and concentrated under vacuum to give the title compound as a white solid (4.7 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]1.[NH2:27][C@@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.C(O)C>>[CH:28]1([NH:27][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[C@@H:15]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]3[C@@H:13]([CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(N)(=O)=O)O[C@H]2n1cnc2c(NC3CCc4ccccc43)ncnc21

Procedure:
2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamide (45.0 mg, 0.000111 mol), (S)-(+)-1-aminoindane (20.0 μL, 0.000156 mol) and N,N-diisopropylethylamine (24.0 μL, 0.000138 mol) were dissolved in ethanol (1.25 mL, 0.0214 mol) and reacted in a microwave at 140° C. for 10 minutes. The mixture was then concentrated in vacuo and used crude in the next step.