Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CC(O)=O.[CH:44]([C:46]1[N:47]([CH2:51][C:52]([NH:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([I:61])[CH:56]=2)=[O:53])[CH:48]=[CH:49][N:50]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[I:61][C:57]1[CH:56]=[C:55]([NH:54][C:52](=[O:53])[CH2:51][N:47]2[CH:48]=[CH:49][N:50]=[C:46]2[CH2:44][N:11]([CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)[CH2:10][CH2:9][C:8]2[CH:38]=[CH:39][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:6][CH:7]=2)[CH:60]=[CH:59][CH:58]=1
Reactant: O=Cc1nccn1CC(=O)Nc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CNCCc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1nccn1CC(=O)Nc1cccc(I)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of di-tert-butyl 2,2′-((2-(2-(((4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (283 mg, 0.50 mmol), AcOH (0.10 mL) and 2-(2-formyl-1H-imidazol-1-yl)-N-(3-iodophenyl)acetamide (178 mg, 0.50 mmol) in DCE (20 mL) at 0° C. was added NaBH(OAc)3 (0.30 g, 1.5 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for overnight and decomposed with water. The reaction mixture was extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by biotage over silica gel eluting with DCM to 40% MeOH in DCM to afford di-tert-butyl 2,2′-((2-(2-((((1-(2-((3-iodophenyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (254 mg, 56%).
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[CH2:1]([Cl:4])[CH:2]=[CH2:3].[NH+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccncc1
Solvent: O
Solvent: C=CCCl
Product: c1cc[nH+]cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
466.5 g of water are placed in the reactor. 229.5 g (3 mol) of allyl chloride are added and the mixture is heated to 50° C. 237.0 g (3 mol) of pyridine are then added dropwise over a period of one hour with vigorous stirring. Following a further eight hours at 50° C. the reaction mixture is subjected to steam distillation at 500 mbar/80° C. During the steam distillation the pH is kept at 5 by means of dilute NaOH. Distillation is continued until the content of pyridine in the bottoms is less than 0.1%. The yield is 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][C@H:28]([CH3:30])[O:27][C@H:26]([CH3:31])[CH2:25]2)=[CH:20][C:19]=1[C:32]1[CH:36]=[CH:35][O:34][C:33]=1[CH3:37].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:30][C@H:28]1[O:27][C@@H:26]([CH3:31])[CH2:25][N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[C:19]([C:32]3[CH:36]=[CH:35][O:34][C:33]=3[CH3:37])[CH:20]=2)[CH2:29]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1occc1-c1cc(N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
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: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2-c2ccoc2C)ccn1
Temperature: 100 °C

Procedure:
2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (313 mg, 1.428 mmol) was added to a solution of cis-4-[4-bromo-3-(2-methyl-3-furanyl)phenyl]-2,6-dimethylmorpholine (500 mg, 1.428 mmol) in a mixture of 1,4-dioxane (6 mL), water (1.000 mL) and sodium carbonate (303 mg, 2.86 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (165 mg, 0.143 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. overnight. Crude LCMS showed starting material and desired product so 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.5 equivalents), tetrakis(triphenylphosphine)palladium(0) (0.05 equivalents) and sodium carbonate (1.0 equivalent) were added and the reaction mixture was stirred and heated at 100° C. in the microwave for a further 1 hour. Crude LCMS showed desired product and no starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by using a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure. This solid was dissolved in 1:1 MeCN:DMSO (3×0.9 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a yellow oil (169 mg, 0.443 mmol, 31.0% yield).
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.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>[F:11][C:10]1[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)=[N:3][C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[C:5]([C:6]([NH2:8])=[O:7])[CH:9]=1
Reactant: CN1CCN(c2ccc(Nc3nc(Cl)c(F)cc3C(N)=O)cc2)CC1
Reactant: OB(O)c1ccncc1
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: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3nc(-c4ccncc4)c(F)cc3C(N)=O)cc2)CC1
Temperature: 90 °C
Yield: 33.3 %

Procedure:
A mixture of 6-chloro-5-fluoro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide (70 mg, 0.192 mmol), pyridin-4-ylboronic acid (23.65 mg, 0.192 mmol), K2CO3 (53.2 mg, 0.385 mmol) and Pd(Ph3P)4 (11.12 mg, 9.62 μmol) in THF (1 mL) was heated at 90° C. overnight in a sealed vial. The reaction mixture was extracted between saturated NaHCO3 and methylene chloride, concentrated and the residue was purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, extracted with methylene chloride, concentrated to give 26 mg of product as orange-red solid. LC-MS: (M+H)+=407.11. 1H NMR (400 MHz, chloroform-d-MIX) δ ppm 8.55-8.60 (2H, m), 7.91 (2H, d, J=5.71 Hz), 7.76 (1H, d, J=11.42 Hz), 7.52 (2H, d, J=9.23 Hz), 6.89 (2H, d, J=8.79 Hz), 3.08-3.16 (4H, m), 2.51-2.60 (4H, m), 2.29 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:4]=12.Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1.C(N(CC)CC)C>CN(C=O)C.CO>[CH3:33][C@H:32]1[C:25]2[C:24]([N:9]3[C:5]4[C:4](=[C:3]([CH2:2][NH:1][C:35]5[N:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH:8]=[CH:7][CH:6]=4)[C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)=[N:29][CH:28]=[N:27][C:26]=2[CH2:30][CH2:31]1
Reactant: Clc1ncccn1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CN)cccc43)c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CNc5ncccn5)cccc43)c21
Yield: 39.4 %

Procedure:
A solution of (R)-tert-butyl 4-(aminomethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (15 mg, 0.033 mmol), 2-chloropyrimidine (3.8 mg, 0.033 mmol), and triethylamine (25 μL, 0.16 mmol) in DMF (0.50 mL) was heated at 100° C. for 24 hours. The material was diluted with MeOH and purified with a Gilson C18 prep HPLC system to give (R)-tert-butyl 1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-((pyrimidin-2-ylamino)methyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (7.0 mg, 0.013 mmol, 40%). LCMS (APCI+) M+H+ 528 (85%); Rt=3.89 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:24][CH2:23][CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: COc1ccc(CCN)cc1
Solvent: O
Product: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (5.0 g, 25.3 mmol), 2-(4-methoxyphenyl)ethanamine (4.2 g, 28 mmol) and 4-N,N-Dimethylaminopyridin (3.3 g; 28 mmol) in methylenehloride (200 ml) was cooled to −10′C. N-ethyl-N′-(3-Dimethylaminopropyl)-carbodiimid hydrochloride (EDC, 5.3 g, 28 mmol) was added in several portions and the resulting mixture stirred overnight. The reaction mixture was poured into water and consecutively extracted with water, 2N NaOH and 1N HCl. Evaporation of the dried (NaSO4) extract yielded an oily residue that crystallized upon addition of n-heptan, which was used without further purification. Yield 7.0 g (21.2 mmol, 83%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5].C1(C)C(S([O-])(=O)=[O:21])=CC=CC=1.[C:25]1([CH3:31])C=CC=CC=1>>[CH3:1][O:2][N:3]([CH3:13])[C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:21][CH2:25][CH2:31][O:12]2)[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Reactant: Cc1ccccc1
Reactant: CON(C)C(=O)C1CCC(=O)CC1
Product: CON(C)C(=O)C1CCC2(CC1)OCCO2
Yield: 38.4 %

Procedure:
A mixture of N-methoxy-N-methyl-4-oxocyclohexanecarboxamide (2.1 g, 0.114 mol), glycol (0.9 g, 0.136 mol) and toluenesulfonate (0.1 g, cat) in toluene (30 mL) was refluxed overnight and then concentrated. Water was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography (CH2Cl2:MeOH=100:1) to give the desired product (1 g, 38.4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@H:11]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[C:12]([OH:14])=O)=[CH:6][CH:5]=1)[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]2[C:7]([CH2:10][C@H:11]([N:15]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:25])[C:12]2=[O:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C[C@@H](C(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOc1ccc2c(c1)C(=O)[C@@H](N1C(=O)c3ccccc3C1=O)C2

Procedure:
(αS)-α-[(4-Ethoxyphenyl)methyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (XIV, EXAMPLE 14, 13.6 g, 40 mmol) is suspended in methylene chloride (40 mL). Trifluoroacetic anhydride (11.4 mL, 80 mmol) is added over 20 min at 20-25°. The resulting mixture is added dropwise to a solution of ferric chloride (6.81 g, 42 mmol) in methylene chloride (80 mL) over 1 hr. After the reaction is complete, it is quenched with water (80 mL). The organic layer is separated and concentrated. The residue is purified with a by column chromatography (silica gel; ethyl acetate/hexane, 20/80) to give the title compound, NMR δ7.85, 177.73, 177.38, 7.26, 5.10, 4.07, 3.52, 3.30 and 1.43; CMR δ200.0, 167.4, 159.0, 143.5, 135.9, 134.1, 132.0, 127.3, 125.3, 123.5, 106.2, 63.9, 54.2, 31.2 and 14.6; HRMS (FAB) calculated for C19H15NO4 [M+1]=322.1079, found=322.1085.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(=O)(O)[O-].[Na+].O.[C:16]([O:20][C:21](=[O:39])[C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]([CH3:37])=[CH:24][C:23]=1[CH3:38])([CH3:19])([CH3:18])[CH3:17]>O1CCOCC1.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:39])[C:22]1[CH:27]=[C:26]([C:4]2[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH2:1])[N:3]=2)[C:25]([CH3:37])=[CH:24][C:23]=1[CH3:38])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(C)c(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2cc(Cl)nc(N)n2)cc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
Commercially available 2-amino-4,6-dichloropyrimidine (460 mg, 2.8 mmol), palladium dichloride-diphenylphosphinoferrocene dichloromethane complex (98 mg, 0.12 mmol), sodium bicarbonate (471 mg, 5.61 mmol), 1,4-dioxane (4.5 ml), and water (2.5 ml) were placed in a reaction vessel. The resulting mixture was stirred at 80° C. for 10 minutes. 2,4-Dimethyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid tert-butyl ester (620 mg, 1.8 mmol) obtained in Step 3 above that was dissolved in 1,4-dioxane (4.5 ml) was added dropwise to the mixture. The resulting mixture was stirred at 80° C. for 19 hours. The reaction solution was diluted with ethyl acetate (150 ml), and washed with water (80 ml) three times and then with a saturated aqueous sodium chloride solution (80 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (30 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=10:1 to 5:1) to yield 5-(2-amino-6-chloropyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (Compound 1-1) (422 mg) as a white solid material.
Reaction SMILES: [C:1]([CH2:3][C:4]1(O)[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH2:6][CH2:5]1)#[N:2].CCN(S(F)(F)[F:35])CC>ClCCl>[F:35][C:4]1([CH2:3][C:1]#[N:2])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH2:6][CH2:5]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CC#N)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CC#N)CC3)c(F)c2)C(=O)O1
Yield: 47 %

Procedure:
The title compound was prepared by stirring (S)-N-{3-[4-(4-cyanomethyl-4-hydroxypiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.45 mmol) with DAST (3.06 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 47% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[BH4-].[Na+].II>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(Br)ccc1Cl
Yield: 97.3 %

Procedure:
5-bromo-2-chlorobenzoic acid (20 g, 84.92 mmol) in dry THF (50 mL) was added to a solution of sodium borohydride (8 g, 212.34 mmol) in dry THF (128 mL) in 15 min at r.t. To the resulting reaction mixture a solution of Iodine (26.85 g, 106.15 mmol) in dry THF (170 mL) was added in another 15 min. Stirring was continued till the Iodine color disappeared after which the reaction mixture was heated to reflux temperature for 18 h. After completion of the reaction as confirmed by TLC, volatiles were evaporated in vacuo. The residue obtained was dissolved in ethyl acetate (200 mL), washed with a saturated solution of NaHSO3 (200 mL) and brine (200 mL) successively. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3:7 Ethyl acetate:Pet. Ether) to afford the title compound (18.3 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][CH:17]([OH:20])[C:18]#[CH:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH:17]([CH3:16])[C:18]#[CH:19])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: C#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)Oc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 150 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 56 mg of 3-butyn-2-ol, to which 32 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 120 mg of 4-(2,3-difluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (134)).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[N:30]1[C:22]([NH:1][C@H:2]([C:4]2[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH3:3])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: C[C@H](N)c1nc2ccc(C#N)cc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(C#N)cc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 37.6 %

Procedure:
A mixture of 2-((S)-1-aminoethyl)-3-phenyl-3H-benzoimidazole-5-carbonitrile from Example 11 (370 mg, 1.4 mmol), 6-chloro-9H-purine (217 mg, 1.4 mmol) and DIPEA (0.36 mL, 2.1 mmol) in n-butanol (2.8 mL) was stirred in a sealed tube for 6 h at 120° C. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in EtOAc followed by gradient 0-10% 2M NH3/MeOH in DCM) affording 122 as a white solid (200 mg, 37%). LCMS: RT 3.29 min [M+H]+ 381.1. 1H NMR (DMSO, 400 MHz): δ 8.21-7.97 (3H, m), 7.84 (1H, d, J=8.35 Hz), 7.72-7.46 (7H, m), 5.49 (1H, br), 1.59 (3H, d, J=6.87 Hz)
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([O:17]C)[CH:6]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N-]=[N+]=[N-]>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:17])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: COc1cc(CN=[N+]=[N-])ccc1-c1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(-c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
4-Azidomethyl-2-methoxy-biphenyl (100 mg, 0.42 mmol) is dissolved in THF (5 mL) and H2O (0.5 mL) and to which PPh3 (100 mg, 0.38 mmol) is added. The mixture is allowed to stir at room temperature overnight. After analysis of TLC suggested the disappearance of the starting azide, the reaction is stopped and THF evaporated. The residue is purified through chromatography to provide the title compound (84 mg, 100%).
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([CH2:9][C@H:10]([O:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])[CH2:11]O)[CH:2]=1.CN(C=O)C.C1CCC(N=C=NC2CCCCC2)CC1>N1C=CC=CC=1>[CH2:11]1[O:18][P:15]([OH:17])(=[O:16])[CH2:14][O:13][C@H:10]1[CH2:9][N:3]1[C:4](=[O:5])[N:6]=[C:7]([NH2:8])[CH:1]=[CH:2]1
Reactant: Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1ccn(C[C@H]2COP(=O)(O)CO2)c(=O)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
cHPMPC was synthesized by adding to a stirred suspension of HPMPC (100 g, 0.358 mol) in DMF (2 L) N, N'-dicyclohexyl-4-morpholinecarboxamidine (115 g, 0.393 mol). The reaction mixture was stirred for 12 hours at room temperature. This solution was added slowly to a hot pyridine solution (5 L, 60° C.) of DCC (185 g, 0.895 mol) through an addition funnel. The reaction mixture was stirred at 100° C. for 16 hours, cooled to room temperature and the solvents were removed under reduced pressure. The crude mixture was washed with diethyl ether (3 L), dissolved in water (2 L) and washed with CH2Cl2 (5×1 L). The aqueous layer was concentrated to 1 L volume and acidified to pH-3.5. Upon cooling cyclic-HPMPC crystallized (89 g,~95% pure). The cHPMPC was recrystallized by dissolving in water at pH8 (with 1N NaOH) followed by acidification to pH 3.5 (with 1N HCl):
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[I:15]Cl>O.Cl>[ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[C:6]([I:15])[C:5]=1[OH:14]
Reactant: CC(C)(C)c1ccc(O)c(CN)c1
Reactant: ClI
Agent: Cl
Solvent: O
Product: CC(C)(C)c1cc(I)c(O)c(CN)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a solution of 2-aminomethyl-4-(1,1-dimethylethyl)phenol hydrochloride (215 g., 1.0 mole) in water (1.6 l.) is added a solution of iodine monochloride (165 g., 1.0 mole) in 3N hydrochloric acid (800 ml.). The resulting reaction mixture is stirred at 20° C. for 3 hours and then cooled to -20° C. whereupon solid is deposited. The deposited solid is collected and crystallized from ethanol 12N-hydrochloric acid (1:1) to give the desired 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (277 g.), m.p. 200°-201° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH:14]=O.CCN(CC)CC.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH2:14][NH:26][CH:23]1[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: CC(=O)NCCc1ccc(Cl)c(C=O)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A mixture of N-[2-(4-chloro-3-formyl-phenyl)-ethyl]-acetamide (50.1 mg, 0.222 mmol), Et3N (0.046 mL, 0.332 mmol) and cyclopropylamine (0.023 mL, 0.332 mmol) in MeOH (0.50 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (21.0 mg, 0.554 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) yielded the title compound (35 mg, 59%). LC-MS: tR=0.59 min; ES+: 267.17.