Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:37]3[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 4-(methanesulfonyl)phenylboronic acid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH2:7]([O:14][C:15]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO)NC(=O)OCc1ccccc1
Yield: 100.3 %

Procedure:
A procedure similar to that described in Preparation 7 was repeated, except that 7.00 g of 2-amino-2-methylpropanol, 13.47 g of benzyloxycarbonyl chloride, 13.13 g of potassium carbonate, 35 ml of ethyl acetate and 35 ml of water were used, to give 17.59 g of the title compound having an Rf value of 0.72 (on silica gel thin layer chromatography, using a 3:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][C:14]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCOC(=O)C1(CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CNc2cc(Br)ccc2[N+](=O)[O-])CC1
Yield: 80.8 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (792 mg, 3.6 mmol) in tetrahydrofuran (30 mL) was added ethyl 1-(aminomethyl)cyclopropanecarboxylate (441 mg, 3.0 mmol) and potassium carbonate (621 mg, 4.5 mmol). The reaction mixture was stirred at reflux for 15 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, concentrated and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give ethyl 1-((5-bromo-2-nitrophenylamino)methyl)cyclopropanecarboxylate as a light yellow solid (832 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:33][C:34]([NH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=[O:35].[CH:42]1([CH2:45][C:46](O)=[O:47])[CH2:44][CH2:43]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:42]1([CH2:45][C:46]([N:39]2[CH2:40][CH2:41][C@@H:37]([NH:36][C:34]([NH:33][C:3]3[CH:4]=[CH:5][C:6]([C:8]([N:10]4[CH2:11][CH2:12][N:13]([CH2:16][C:17]5[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:21][CH:22]=5)[CH2:14][CH2:15]4)=[O:9])=[CH:7][C:2]=3[F:1])=[O:35])[CH2:38]2)=[O:47])[CH2:44][CH2:43]1
Reactant: O=C(O)CC1CC1
Reactant: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@@H]1CCNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@@H]1CCN(C(=O)CC2CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a stirring solution of (R)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyrrolidin-3-yl)urea (0.123 mmol, 73 mg), 2-cyclopropylacetic acid (0.123 mmol, 12.4 mg) and triethylamine (0.370 mmol, 35.5 mg) in dichloromethane (2 mL) was added 1-propanephosphonic acid cyclic anhydride (0.370 mmol, 118 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (2 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (3 mL). The organic phase was concentrated and the resulting residue was purified by HPLC and then treated with strong cation exchange column chromatography to afford the title compound (28 mg). MS (ESI) m/z 674.3 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([O:25][CH3:26])[NH:22]3)=[C:18]([NH2:27])[N:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[CH:8]1([CH2:14][O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([O:25][CH3:26])[N:22]3[CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:18]([NH2:27])[N:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COc1nc2c(N)nc(OCC3CCCCC3)nc2[nH]1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCC3CCCCC3)nc2n1CC1CCOCC1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-8-(methoxy)-9H-purin-6-amine trifluoroacetate salt (0.28 g) was heated with anhydrous potassium carbonate (0.3957 g) in anhydrous DMF (5 mL) under nitrogen for 1 hour at 60° C. (external). The reaction mixture was cooled to room temperature before adding 4-(bromomethyl) tetrahydro-2H-pyran (0.14 g) in anhydrous DMF (1 mL). The reaction mixture was heated to 50° C., overnight. The reaction mixture was quenched into water (20 mL) and extracted into ethyl acetate (20 mL, 3 times). The organic layers was separated, combined and then washed with brine (20 mL). The organic layer was separated and then dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave pale yellow oil that solidified on standing. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (30-80%) to give the title compound as a white solid (0.1677 g).
Reaction SMILES: Br[C:2]1[O:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>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>[CH3:12][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][O:6][C:2]=1[CH:13]=[CH2:14]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1noc(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1onc(C(=O)OCC)c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (15 g, 64.1 mmol) and tributyl(vinyl)stannane (22.48 mL, 77 mmol) were stirred in dry dioxane (250 mL) and purged with nitrogen for 90 minutes at room temperature. Tetrakis(triphenylphosphine)palladium (3.70 g, 3.20 mmol) was added and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was partitioned in ethyl acetate (250 mL) and water (250 mL) and separated. To the organic layer was added sodium fluoride solution (˜1M, 250 ml) and the resulting suspension was filtered through Celite®. The layers were separated and the organics were washed with water, brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-30% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>COCCOC.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:23])[CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
To a solution of ester 318 (7.50 g, 27.2 mmol) in dry DME (125 mL) at 0° C. was added triethylamine (6.0 mL, 4.3 g, 43 mmol), copper (I) iodide (1.00 g, 5.25 mmol), and bis(triphenylphosphine) palladium (II) chloride (0.65 g, 0.93 mmol). The mixture was degassed with a stream of N2 for 5 min, then trimethylsilylacetylene (5.8 mL, 4.1 g, 41 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 24 h. It was concentrated under reduced pressure, partitioned between ethyl acetate and water, washed with brine, dried (anhydrous MgSO4), filtered and concentrated. Flash chromatography of the residue (eluent 4% ethyl acetate/hexanes) afforded title compound 319 (4.65 g, 69% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.22 (dd, J=7.4, 0.8 Hz, 1H); 7.07-6.95 (m, 3H); 3.58 (s, 2H); 3.45 (s, 3H); 0.00 (s, 9H). LCMS: (M+H) 247.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>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.O1CCOCC1.O>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:3]=2)[CH:19]=[N:18]1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Oc3ccc(N)nc3)ncn2)cn1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
A mixture of 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (0.50 g, 2.25 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.47 g, 2.25 mmol), and Cs2CO3 (1.46 g, 4.49 mmol) in 5:1 dioxane/water (6 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.26 g, 0.23 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, the solids removed via filtration, washed with dioxane and the filtrate concentrated to dryness. The residue was treated with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to dryness. The material was treated with EtOAc and the resulting solid collected via filtration to afford 5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (0.41 g, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (d, 1 H), 8.44 (s, 1 H), 8.12 (s, 1 H), 7.78 (d, 1 H), 7.28 (m, 2 H), 6.48 (d, 1 H), 5.94 (s, 2 H), 3.88 (s, 3 H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH3:5][C:6]([Si:9](Cl)([CH3:11])[CH3:10])([CH3:8])[CH3:7].N#N.Cl>N1C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][Si:9]([C:6]([CH3:8])([CH3:7])[CH3:5])([CH3:11])[CH3:10])[C:2]#[CH:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCO
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCO[Si](C)(C)C(C)(C)C
Reaction time: 72 h

Procedure:
To a solution of 5.82 mL of propargyl alcohol in 20 mL of pyridine and 30 mL of CH2Cl2 was added 0.122 g of DMAP and 16.88 g of TBDMSCl in a N2 atmosphere. After stirring 3 days, the reaction was poured into 100 mL of 1N HCl, and diluted with CH2Cl2. The layers were separated and the organic layer washed with 100 mL of 1N HCl (2×), 10% NaHCO3, H2O and brine and dried (MgSO4). Filtration and concentration provided 15.07 g of an oil which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][N:6]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>C(#N)C>[CH3:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][NH:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])=[CH:5][N:6]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Cc1ncc(CNCCCN)s1
Solvent: CC#N
Product: Cc1ncc(CN2CCCNC2=C[N+](=O)[O-])s1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
N-(2-Methyl-5-thiazolylmethyl)trimethylenediamine (18.5 g) was dissolved in 100 ml of acetonitrile, and 1-nitro-2,2-bis(methylthio)ethylene (16.5 g) was added. With stirring, the mixture was refluxed for 6 hours. After the reaction, the reaction mixture was cooled to room temperature. The resulting crystals were collected by filtration and washed with methanol to give 10.2 g of the desired 1-(2-methyl-5-thiazolylmethyl)2-(nitromethylene)tetrahydropyrimidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:18](O)(=O)C.O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+]>ClCCl.CO>[CH3:18][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: NC(=O)c1ccc(C2CCNCC2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(C(N)=O)cc2)CC1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 4-piperidin-4-ylbenzamide (200 mg, 1.00 mmol), 37% aqueous formaldehyde (162 μL, 2.00 mmol), and acetic acid (86 uL, 1.5 mmol) in a mixture of dichloromethane and methanol (2:1, 6 mL) was added sodium triacetoxylborohydride (318 mg, 1.5 mmol) in portions over fifteen minutes and stirring was continued for 2 hr at room temperature. The reaction was then quenched with water and adjusted to pH 9 with 2N aqueous sodium hydroxide then extracted with dichloromethane (2×50 ml). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated to give 4-(1-methylpiperidin-4-yl)benzamide (190 mg, 87%). MS (EI) for C13H18N2O: 218 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:15]=[N:14][C:13](O)=[CH:12][CH:11]=1.P(Cl)(Cl)([Cl:19])=O>C(Cl)CCl>[Cl:19][C:13]1[N:14]=[N:15][C:10]([C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2nc3ccccc3[nH]2)nn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Clc1ccc(-c2nc3ccccc3[nH]2)nn1
Yield: 20 %

Procedure:
6-(1H-Benzoimidazol-2-yl)pyridazin-3-ol (0.322 g, 1.570 mmol) was suspended in ethylene dichloride (10 mL). Phosphorus oxychloride was added (15 mL) and the mixture was stirred at reflux for 48 hours. All solvents were removed and the residue was washed with saturated NaHCO3 and extracted with ethyl acetate. The organic solution was dried, concentrated and purified by column chromatography to yield 0.075 g of 2-(6-chloro-pyridazin-3-yl)-1H-benzoimidazole (0.32 mmol, 20% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14]1.[Br:25][C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[Cl:34].[Cl-].[NH4+]>C1COCC1>[Br:25][C:26]1[CH:31]=[C:30]([CH2:32][CH:17]([CH:13]2[CH2:14][CH2:15][CH2:16]2)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:29]=[CH:28][C:27]=1[Cl:34]
Reactant: Clc1ccc(CBr)cc1Br
Reactant: CC(C)(C)OC(=O)CC1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(Br)c1)C1CCC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Under argon, 2.9 ml (20.8 mmol) of diisopropylamine were dissolved in 30 ml of dry THF, and the mixture was cooled to −20° C. 8.3 ml (20.8 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise, and the resulting mixture was stirred to −20° C. for 30 min and then cooled to −78° C. At this temperature, a solution of 2.60 g (about 15.3 mmol, crude) of tert-butyl cyclobutylacetate in 10 ml of THF was added. After 4 h of stirring at −78° C., a solution of 3.95 g (13.9 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 10 ml of THF was added. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The solid that remained was triturated with 30 ml of cyclohexane/dichloromethane (1:1) and filtered off. The solid was once more triturated with 10 ml of cyclohexane/dichloromethane (1:1) and again filtered off; this procedure was repeated once more. All filtrates were collected, combined and concentrated under reduced pressure. This residue was then purified further by chromatography on silica gel (mobile phase from pure cyclohexane to cyclohexane/dichloromethane 20:1 to 10:1). This gave 2.24 g of the title compound (43.2% of theory).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 70 %

Procedure:
To a solution of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (30.7 g, 93.7 mmol) in IPA (300 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (26.9 g, 112.5 mmol) and DIPEA (48 mL, 281.2 mmol) and the reaction mixture heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (600 mL). The solution was washed with water and the organic fraction separated. The organic fraction was washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to yield the title compound as a yellow oil (30 g, 70%) 1H NMR 400 MHz (CDCl3) δ 8.25 (1H, s), 7.96 (1H, s), 7.70 (1H, qn, J=4.1 Hz), 7.37-7.58 (5H, m), 6.98-6.82 (1H, m), 6.52-6.66 (1H, m), 5.60-5.77 (2H, m), 4.12-4.19 (1H, m), 3.76 (1H, td, J 11.3, 2.5 Hz), 1.91-2.13 (4H, m), 1.68-1.84 (2H, m), 1.60-1.68 (3H, m)
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.C(O)(=O)C>C1COCC1.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Agent: [Pd+2]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2cccnc2F)CC1
Reaction time: 5 h

Procedure:
1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.14 g, 0.65 mmol), palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 ne/w (91 mg, 0.13 mmol) and acetic acid, glacial (19 uL, 0.32 mmol) were suspended in THF (13 mL) in a pressure tube. The reaction mixture was hydrogenated at 50 psi for 5 h then filtered through a pad of celite and washed with THF. The filtrate was concentrated to give 1-(4-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone as clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:13]=[O:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:13]=[O:14])[C:11]=1[O:12][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(O)c(C=O)c1
Reactant: COCCOCCl
Product: COCCOCOc1c(Br)cc(C(=O)OC)cc1C=O
Yield: 96 %

Procedure:
Proceeding as in Reference 12, but substituting methyl 3-bromo-5-formyl-4-hydroxybenzoate (12.6 g, 48.6 mmol, 1.0 eq.) and methoxyethoxymethyl chloride (6.8 mL, 7.26 g, 58.3 mmol, 1.2 eq.), gave methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-benzoate (16.2 g) as a colorless oil which solidified upon standing.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[BH3-]C#[N:14].[Na+]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:14]
Reactant: [BH3-]C#N
Reactant: Cc1cccc2c1CCC2=O
Agent: [Na+]
Product: Cc1cccc2c1CCC2N

Procedure:
The title amine was generated from 4-methyl-indan-1-one (5.00 g, 34.20 mmol), NaBH3CN (15.00 g, 0.24 mol) and NH4OAc (79.00 g, 1.02 mol) according to the protocols as outlined in general procedure B described above.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[SH2:9]>C(N(CC)CC)C>[NH2:6][C:5](=[S:9])[CH2:4][C:3]([N:2]([CH3:8])[CH3:1])=[O:7]
Reactant: S
Reactant: CN(C)C(=O)CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CC(N)=S
Temperature: 55 °C
Reaction time: 12 h

Procedure:
A reaction mixture was prepared from 22.4 g. of N,N-dimethylcyanoacetamide, 21 ml. of liquid hydrogen sulfide and 1 ml. of triethylamine. The reaction mixture was placed in an autoclave and the autoclave shaken at about 55° C. for about 12 hours. The reaction mixture was taken from the autoclave and the volatile constituents removed by evaporation. Ethanol was added to the residue, thus producing a crystalline solid. The solid was filtered and the filter cake washed with cold ethanol. Twenty-one grams of 3-amino-3-thioxo-N,N-dimethylpropanamide were obtained melting at 111°-114° C. The compound had the following nmr (CDCl3 +DMSOd6):δ3.07 (doublet, 6H); 3.82 (singlet, 2H); 9.1 (very broad, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:23])=[CH:20][N:19]=2)[CH:17]=1
Reactant: CC(C)N
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: CC(C)NC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4F)nnn3C)c2)nc1
Yield: 61 %

Procedure:
As described for example 22, 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (75 mg, 0.194 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (51 mg, 61%) which was obtained as an off white foam. MS: m/e=406.3 [M+H]+.