Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([Cl:10])=[CH:6][C:7]=1[NH:8][CH3:9].[CH2:13](Cl)Cl>C(O)(=O)C.C(OCC)(OCC)OCC.C(OCC)(=O)C>[Cl:10][C:5]1[N:4]=[C:3]([C:11]#[N:12])[C:2]2[N:1]=[CH:9][N:8]([CH3:13])[C:7]=2[CH:6]=1
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: Cn1cnc2c(C#N)nc(Cl)cc21
Temperature: 150 °C

Procedure:
The suspension of 3-amino-6-chloro-4-methylamino-pyridine-2-carbonitrile (1.8 g) in DCM (5 ml), acetic acid (1.5 ml) and triethyl orthoformate (10 ml) was heated in microwave at 150° C. for 30 minutes. The mixture was then diluted with ethyl acetate (200 ml), washed with 10% sodium carbonate (100 ml), dried over sodium sulphate, solvent removed under reduced pressure, DCM (5 ml) was then added to the residue, some product crashed out and collected by filtration (0.5 g), the rest was then columned on silica gel using ethyl acetate-heptane (55:45) as eluant to give another 0.8 g of expected product (a total of 1.3 g product). 1H NMR (CDCl3) δ: 8.1 (s, 1H), 7.6 (s, 1H), 3.93 (s, 3H). MS m/z 193 (M+H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:6]([OH:13])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.CO>O=[Pt]=O.O>[ClH:1].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C:3]2[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=2[OH:17])[CH:6]([OH:13])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:22][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(N)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2cc(C(O)CNC(C)(C)C)ccc2O)cc1

Procedure:
A mixture of 3-amino-4-hydroxy-α-(tert.butylaminomethyl)-benzylalcohol hydrochloride (6.53 g, 0.025 mole), p-methoxybenzaldehyde (3.4 g, 0.025 mole), PtO2 (180 mg), and methanol (125 ml) was placed in a hydrogenation apparatus and hydrogenated at normal pressure (20 - 30 cm H2O superatmospheric) for one hour and 50 minutes. During this period of time, the calculated amount of hydrogen was absorbed, and the hydrogenation was interrupted by supplying argon. The platinum catalyst was filtered off with continued supply of argon, but in spite of this, the filtrate quickly became dark due to oxidation. The filtrate was immediately evaporated in vacuum at 40° - 50° C. The residue which was a light brown foam (9.53 g), was recrystallized twice by precipitation from ethanol/ether (1:1). The yield of the analytical pure 3-(4-methoxybenzylamino)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride was 5.2 g (55%), m.p. 196.6° - 197.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[NH:10]1[CH2:20][CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11]1>CC#N>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:20][CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CC#N
Product: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
4-chlorobenzyl chloride (6.42 g, 39.9 mmol) and 1Pr2NEt (7.74 g, 40.0 mmol) were added to a solution of ethyl nipecotate (6.29 g, 40.0 mmol) in CH3CN (15 mL). The reaction mixture was stirred at 70° C. for 1.5 h. The solvent was removed under reduced pressure. Saturated aqueous NaHCO3 (50 mL) was added to the residue and the mixture was extracted with EtOAc (100 mL). The organic phase was washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to afford ethyl 1-(4-chlorobenzyl)nipecotate as a red yellow oil (11.025 g, 97.8%) used without further purification. The purity was determined by RPLC/MS (97%); ESI/MS m/e 382.2 (M++H, C15H21ClNO2).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1I)=[O:4].CC([O-])=O.[K+].[CH:24]1[CH:29]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:25]=1>CN(C)C=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:29][C:24](=[CH2:25])[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(I)c(CCNC(=O)C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=C1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Reaction time: 8 h
Yield: 462.7 %

Procedure:
A solution of N-allyl, N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (20.5 g, 50 mmol) in dimethylformamide (250 mL) is treated with KOAc (14.6 g, 149 mmol), n-Bu4NBr (16.0 g, 50 mmol), PPh3 (1.3 g, 5.0 mmol), Pd(OAc)2 (0.56 g, 2.5 mmol) and stirred overnight at 90 C. The product mixture was cooled to 20 C, filtered, diluted with water (500 mL) and extracted with ether (3×500 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexane, silica) resulted in 6.6 g of a yellow oil. 1H NMR (400 MHz, CDCl3) d 7.26 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 6.66 (s, 1H), 5.34-5.19 (m, 2H), 4.40 (m, 2H), 3.83 (m, 2H), 3.80 (s, 3H), 3.00 (m, 2H). MS calculated for C14H14F3NO2+H: 285, observed: 285.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(CCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc(CCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5.08 g (9.81 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{[p-(2-phenylethyl)phenyl]methyl}hexanoic acid in 22 ml of DMF are silylated, under a protective gas, with 6.80 g (45.1 mmol) of tert-butyldimethylchlorosilane and 5.48 g (80.4 mmol) of imidazole at RT for 20 h. The reaction mixture is poured onto 500 ml of ice-water, and this mixture is extracted 3× with ethyl acetate. The organic phases are washed with 10% citric acid solution, 2× water and saline, dried with Na2SO4 and evaporated. The residue is dissolved in 119 ml of methanol and 46 ml of THF, and this solution is treated with 8.1 g of potassium carbonate and 46 ml of water, and then stirred at RT for 17 h. The reaction mixture is subsequently poured onto ice-cold 10% citric acid solution, and this mixture is extracted 3× with ethyl acetate. The organic phases are washed with 2 portions of water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate 2:1→1:1→ethyl acetate) results in the pure title compound: TLC Rf (D)=0.22; tRet (II)=23.3 min.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH2:20]([N:27]([CH3:36])[C:28](N1C=C[N+](C)=C1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28](=[O:29])[N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:36])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CN(Cc1ccccc1)C(=O)n1cc[n+](C)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, (1:5) (69%, colourless oil) HPLC-MS m/z=403.2 (M+1), Rt: 5.11 min
Reaction SMILES: C[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH2:16])=[N:13][N:12]=3)[CH:9]=2)[NH:4][N:3]=1.BrC1C=CC(F)=C(C=1)C=O>>[NH:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]3[S:15][C:14]([NH2:16])=[N:13][N:12]=3)=[CH:7][CH:6]=2)[CH:2]=[N:3]1
Reactant: Cc1n[nH]c2ccc(-c3nnc(N)s3)cc12
Agent: O=Cc1cc(Br)ccc1F
Product: Nc1nnc(-c2ccc3[nH]ncc3c2)s1

Procedure:
5-(1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine was synthesized in a way similar to that of 4f as shown in Scheme 3 with commercially available 5-bromo-2-fluorobenzaldehyde as the starting material in three steps. MS (API-ES) m/z (%): 218 (100%, M++1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14](Cl)[N:13]=[CH:12][N:11]=1>O1CCCC1>[CH3:7][O:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=[CH:12][N:11]=1
Reactant: C1CCNCC1
Reactant: COCc1ncnc(Cl)c1C
Solvent: C1CCOC1
Product: COCc1ncnc(N2CCCCC2)c1C
Reaction time: 8 h

Procedure:
Piperidine (15 ml) in tetrahydrofuran (40 ml) was added dropwise to a solution of 4-methoxymethyl-5-methyl-6-chloropyrimidine (5 g) in tetrahydrofuran (40 ml). The mixture was heated under reflux for 7 hours and then allowed to stand overnight at room temperature. It was filtered, stripped, and water added to the residual oil. The pH was lowered to 7.5 (HCl) and extracted with chloroform. Extracts were dried (K2CO3) and stripped to give 4-methoxymethyl-5-methyl-6-piperidinopyrimidine, 6.08 g, as an oil, which solidified on cooling to 5° (m.p. 45°-47°). It was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][C:42]=2[CH:44]=[O:45])[CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:44](=[O:45])[C:42]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:43]=2[N:34]=[CH:35][CH:36]=[CH:37]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC(=O)OC(C)(C)C)c2ccc(F)cc2)cc1
Reactant: O=Cc1cccc2cccnc12
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)c1cccc2cccnc12)c1ccc(F)cc1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
1.9 g (5.1 mmol) of tert-butyl [(4-fluorophenyl)(toluene-4-sulfonyl)methyl]carbamate, 255 mg (1.0 mmol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, 10.5 ml (76 mmol) of triethylamine and 0.72 g (4.55 mmol) of 8-quinolinecarbaldehyde were mixed in 44 ml of methylene chloride at room temperature and then heated at 35° C. for 3 h. After reaction of the aldehyde was complete, 25 ml of saturated ammonium chloride solution were added, and the reaction mixture was stirred for 15 minutes. After removal of the aqueous phase, the organic phase was washed with 0.5 M sodium hydroxide solution and saturated sodium chloride solution, and 1.7 g of tert-butyl [1-(4-fluorophenyl)-2-oxo-2-quinolin-8-ylethyl]carbamate were obtained and were reacted further without purification.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][C:23]#[C:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34].C(N(CC)C(C)C)(C)C>ClCCl>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][C:23]#[C:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1OCC#CCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1OCC#CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 64.7 %

Procedure:
Into 35 ml of dichloromethane were dissolved 2.67 g of 4-diphenylmethoxypiperidine, 2.93 g of 1-chloro-4-(2-nitrophenoxy)-2-butyne and 1.68 g of N,N-diisopropylethylamine, and the resultant solution was stirred at room temperature for 20 hours. The reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with ethyl acetate by silica gel column chromatography to give 2.95 g of oily 4-diphenylmethoxy-1-[4-(2-nitrophenoxy)-2-butynyl]piperidine.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[C:15]([C:17]([C:23]#[N:24])=[C:18]([NH:21][CH3:22])SC)#[N:16]>C(#N)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:18]([NH:21][CH3:22])=[C:17]([C:23]#[N:24])[C:15]#[N:16])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Reactant: CNC(SC)=C(C#N)C#N
Solvent: CC#N
Product: CNC(NCCCCc1csc(NC(=N)N)n1)=C(C#N)C#N

Procedure:
A mixture of 2-guanidino-4-(4-aminobutyl)thiazole (0.43 g.) and 1,1-dicyano-2-methylamino-2-methylthioethylene (0.3 g.) in acetonitrile (10 ml.) was heated under reflux for 16 hours. The mixture was then evaporated to dryness and the resulting gum purified by chromatography on a silica column using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.5 v/v/v as developing solvent to give 1-[4-(2-guanidinothiazol-4-yl)butylamino]-1-methylamino-2,2-dicyanoethylene.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])=[O:46]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])=[O:46])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(2-chlorophenyl)ethanone and isolated as yellow gum. MS(m/e): 435.3 (MH+).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1)=[O:2].[Cl:13][C:14]1[CH:15]=[N:16][C:17](I)=[N:18][CH:19]=1.C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[Cl:13][C:14]1[CH:15]=[N:16][C:17]([CH:1]([OH:2])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]2)=[N:18][CH:19]=1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: Clc1cnc(I)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(O)c2ncc(Cl)cn2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a mixture of methyl trans-4-formylcyclohexanecarboxylate (150 mg, 0.88 mmol) and 5-chloro-2-iodopyrimidine (210 mg, 0.88 mmol) in THF (4 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 0.35 mL, 0.88 mmol) dropwise. The reaction mixture was stirred at −78° C. for 2 hours and then saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to afford methyl trans-4-[(5-chloropyrimidin-2-yl)(hydroxy)methyl]cyclohexanecarboxylate. MS ESI calc'd for C13H18ClN2O3 [M+H]+ 285. found 285. 1H NMR: (400 MHz, CDCl3) δ 8.70 (s, 2H), 4.68 (s, 1H), 3.65 (s, 3H), 2.24 (s, 1H), 2.03-1.82 (m, 3H), 1.48-1.42 (m, 3H), 1.31-1.27 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(B(O)O)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1>CCO.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC.[Cl-].[Na+].O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)n2)CC1
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: [Cl-]
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)n2)CC1
Temperature: 80 °C
Yield: 74.6 %

Procedure:
To a mixture of 5-amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (331 mg, 0.93 mmol) (as prepared in Example 54, step (c)) and cyclohexen-1-yl boronic acid (141 mg, 1.11 mmol) in 5 mL of EtOH, 10 mL of toluene and 5 mL of 2 M Na2CO3, was added Pd(PPh3)4 (107 mg, 0.0930 mmol) and the result was heated at 80° C. for 16 h. The reaction was diluted with 100 mL of ether and 100 mL of brine and the layers were separated. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue by column chromatography (silica gel, 30-60% ether-hexanes) afforded 248 mg (74%) the title compound as an light brown oil LC-MS (ESI, m/z): Calcd. for C21H32N3O2 (M+H), 358.2. found 358.1.
Reaction SMILES: NC1N=CC([C:8]2[C:9]([CH:26]=[O:27])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:12]=2)=CC=1C1OC2C=CC=CC=2N=1.[Br:37]C1C=NNC=1C=O.C(=O)([O-])[O-].[K+].[K+].CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O>C(#N)C>[Br:37][C:8]1[C:9]([CH:26]=[O:27])=[N:10][N:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:12]=1
Reactant: O=Cc1[nH]ncc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(C=O)n2)CC1

Procedure:
Sodium tetrahydroborate (42.6 mg) and tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (550 mg) in methanol (10 ml) were stirred at room temperature for 1 hour. The reaction was incomplete and further sodium tetrahydroborate (42.6 mg) was added at room temperature and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water (2×20 ml), dried over magnesium sulfate and concentrated to dryness. The residue was dissolved in dichloromethane (2 ml) and the solution was cooled to 0° C. and treated with trifluoroacetic acid (3 ml). The resulting solution was allowed to stir at room temperature for 1 hour and then concentrated to dryness. The residue was re-dissolved in methanolic ammonia (7N, 5 ml) and absorbed onto silica and purified by flash chromatography on silica gel eluting with 0 to 15% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol (440 mg) as a solid. The tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate used as starting material was prepared as follows: 4-bromo-2H-pyrazole-3-carbaldehyde (3 g), potassium carbonate (3.32 g) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (6.23 g) in acetonitrile (150 ml) were stirred at reflux overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to yield tert-butyl 4-(4-bromo-3-formyl-pyrazol-1-yl)piperidine-1-carboxylate (4.10 g) as a clear colourless oil which crystallised on standing. NMR Spectrum: (CDCl3) 1.48 (s, 9H), 1.92 (dd, 1H), 1.96 (dd, 1H), 2.10-2.18 (m, 2H), 2.81-2.97 (m, 2H), 4.27 (bs, 2H), 4.28-4.38 (m, 1H), 7.543 (s, 1H), 9.96 (s, 1H); Mass spectrum: M+H+ 360.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:20])C(=O)C1.[CH3:21][C:22]([Si:25]([CH3:35])([CH3:34])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])([CH3:24])[CH3:23]>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][Si:25]([C:22]([CH3:21])([CH3:23])[CH3:24])([CH3:34])[CH3:35]
Reactant: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
Add TBDMSCl (4.6 g, 30.5 mmol) to a solution of o-cresol (3 g, 28 mmol) and imidazole (2.08 g, 30.5 mmol) in 25 ml of dry DMF and stir at room temperature. After 7 h, pour the reaction into H2O and extract with hexane twice. Combine the organic layers, wash with H2O, dry over Na2SO4, filter and concentrate under reduced pressure to give a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford pure (1,1-dimethylethyl)dimethyl(2-methylphenoxy)silane as colourless oil. Add AIBN (330 mg, 1.98 mmol) to a solution of NBS (3.87 g, 21.76 mmol) and (1,1-dimethylethyl)dimethyl(2-methylphenoxy)silane (4.4 g, 19.78 mmol) in 100 ml of CCl4 and stir at reflux for 6 h. Concentrate the solvent under reduced pressure, add hexane and filter the solid. Wash the hexane with a saturated aqueous solution of NaHCO3 and H2O. Dry the organic phase over Na2SO4, filter and concentrate under reduced pressure to obtain [2-(bromomethyl)phenoxy](1,1-dimethylethyl)dimethylsilane as colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:23]([CH3:24])[CH3:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc2c(s1)C(N(C)C)COc1ccc(Br)cc1-2
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (200 mg, 0.477 mmol) in THF (6 mL) were added Dimethylamine Hydrochloride (77.8 mg, 0.954 mmol), DIPEA (308 mg, 2.38 mmol). The reaction mixture was stirred in autoclave at 60° C. overnight. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-Bromo-4-dimethylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (120 mg, 65%).