Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:5]=[C:6]([CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[C:36]=1[OH:37])[CH2:7][C@@H:8]([CH2:13][C:14](=[O:33])[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[NH:23][C:22]2=[O:32])[CH2:17][CH2:16]1)[C:9]([O:11]C)=[O:10]>O.C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:34]=[C:35]([C:38]([F:41])([F:39])[F:40])[C:36]=1[OH:37])[CH2:7][C@@H:8]([CH2:13][C:14](=[O:33])[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH2:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[NH:23][C:22]2=[O:32])[CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 115 mg (4.80 mmol) LiOH in 50 mL water was added to a solution of 1.80 g (3.17 mmol) methyl (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoate in 50 mL THF and the reaction mixture was stirred overnight at RT. The reaction solution was freed from the THF i.vac., diluted with 150 mL water, the aqueous phase was washed with 150 mL EtOAc, acidified with concentrated HCl, extracted with 150 mL EtOAc, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the product was further reacted without purification.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])[CH3:29].O>CN(C)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>[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:28](=[O:30])[CH3:29])=[CH:32][CH:33]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
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: O
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 120 °C
Yield: 96.9 %

Procedure:
Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (921 mg, 3.0 mmol) in N,N-dimethylacetamide (6 mL). Add potassium carbonate (996 mg, 7.2 mmol), 4-acetylbenzene boronic acid (590 mg, 3.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0174 g, 0.015 mmol), then water (3 mL). Heat at 120° C. for 17 hr., then cool to room temperature, add water (15 mL) and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®. Concentrate the filtrate and purify by SCX-2® chromatography washing with methanol then eluting with 3.5 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 5:95 to 20:80 methanol:DCM), to give 1-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-ethanone as a yellow powder (1.135 g, 97%). MS (ES): m/z=391 [M+H]+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1>ClCCl>[Br:1][C:13]1[CH:12]=[N:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CSc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: CSc1ccc(-c2c(Br)cnn2-c2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A solution of bromine (0.9 g) in dichloromethane (2 ml) was added dropwise to an ice-cooled solution of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole (1.6 g) in dichloromethane (10 ml). The mixture was stirred at 5° C. for 1 hour, washed with a solution of sodium bisulfite and water, dried, and concentrated in vacuo. The residue (1.9 g) was recrystallized from ethanol to give crystals of 4-bromo-1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole (1.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.[N:14]1([CH2:19][C:20]2([CH2:23][NH2:24])[CH2:22][CH2:21]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:24][CH2:23][C:20]2([CH2:19][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:21][CH2:22]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: NCC1(CN2CCCC2)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCC2(CN3CCCC3)CC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
4-amino-2-fluoro-5-methoxy-benzoic acid (Intermediate 183; 500 mg, 2.70 mmol), [1-(pyrrolidin-1-ylmethyl)cyclopropyl]methanamine (Intermediate 33; 417 mg, 2.70 mmol), HATU (1.545 g, 4.05 mmol) and DIPEA (1.415 mL, 8.10 mmol) were dissolved in DMF (8 mL) and left to stir for 3 hours at room temperature. The reaction mixture was loaded onto an SCX-3 column pre-washed with methanol. The column was washed with methanol eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated and the residue purified on a silica column (5-12% MeOH ammonia/DCM gradient elution) to yield the title compound as an orange-brown solid (200 mg, 23%).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][N:5]=1)[CH3:3].Cl[C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[F:35][C:32]1[CH:33]=[C:34]2[C:29]([CH2:28][CH2:27][N:26]2[CH:23]2[CH2:24][CH2:25][N:20]([C:17]3[N:18]=[N:19][C:14]([C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:6]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[CH:30][CH:31]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: CN(C)c1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 2-(N,N-dimethylamino)pyridine-5-boronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: COC1C=CC([C@@H]2C(=O)N([C@@H]([C@H](C3C=CC=CC=3)C)C([NH:18][C:19]3[S:20][CH:21]=[C:22]([C:24](=[O:27])CC)[N:23]=3)=O)C(=O)N2)=CC=1.[CH3:37][O-:38].[Na+]>CO>[CH3:37][O:38][C:24]([C:22]1[N:23]=[C:19]([NH2:18])[S:20][CH:21]=1)=[O:27]
Reactant: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1csc(N)n1

Procedure:
2-Amino-thiazole-4-carboxylic acid ethyl ester (38 g) (prepared as described in Example 4) in methanol (400 mL) was cooled in an ice bath and to it was added 25% sodium methoxide over 0.5 hours. The ice bath was removed after 0.5 hours. A small amount of isoluble material was removed by filtration and to the yellow solution was added saturated aqueous ammonium chloride and the reaction mixture concentrated to remove excess methanol. The mixture was basified to pH=9.0 with saturated aqueous sodium bicarbonate and extracted with 1:1 ether/tetrahydrofuran (3×200 mL). The combined organic extracts were washed with water. The organic solution was dried over sodium sulfate and concentrated to give a pale yellow solid which still contained some residual solvent. The solid was suspended in hexanes, filtered on a 5.5 cm funnel then dried in vacuo to give 2-amino-thiazole-4-carboxylic acid methyl ester (15.6 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:39][CH:40]=1)(=[O:31])=[O:30]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (3.83 g, 0.0153 mol; Icagen) was dissolved in THF (70 mL, 0.8 mol) and cooled in an ice bath. 1.0 M of Lithium hexamethyldisilazide in THF (33 mL) was added dropwise to the reaction. After 30 minutes, a solution of 4-(chlorosulfonyl)benzoic acid (3.07 g, 0.0139 mol) in THF (30 mL, 0.4 mol) was added dropwise to the reaction. The reaction was stirred overnight then quenched with 0.5 N HCl and diluted with ethyl acetate. The phases were separated and the organic phase was washed with 2× with 0.5N HCl. The organic phase was dried over magnesium sulfate, treated with activated carbon and filtered through Celite. The filtrate was evaporated to a residue and triturated with ethyl acetate. The solid was collected by filtration. Vacuum drying afforded the product as a tan solid (2.55 g, 40%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1>C1COCC1>[F:17][C:18]1[CH:23]=[C:22]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:20][CH:19]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2cccc(F)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (41 mg, 0.20 mmol) in THF (2 mL) at −78° C. was added 1.0 M 3-fluorophenylmagnesium bromide in THF (0.4 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3-fluoro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:25])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 92 %

Procedure:
As described for example 84f, 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (110 mg, 92%) which was obtained as a colourless oil. MS: m/e=412.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14]([C:20]#[C:19][C:21]4[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Reactant: C#Cc1cnc(N)nc1
Product: Nc1ncc(C#Cc2cnc3c(F)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-fluoro-3-iodo-imidazo[1,2-a]pyridine (example C.30 step 2) (300 mg, 0.8 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (115 mg, 0.8 mmol) according to general procedure II. Obtained as an off-white solid (101 mg, 34%). MS (ISP) 364.1 [(M+H)+],366 [(M+2+H)+]; mp 279–280° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccnc(CBr)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.8 %

Procedure:
A solution of 2-methyl-4-nitropyridine (1.79 g, 13.0 mmol) in CCl4 (30 mL) was treated with N-bromosuccinimide (2.31 g, 13.0 mmol) and benzoyl peroxide (420 mg, 1.30 mmol), stirred at 80° C. for 16 h, cooled to room temperature, filtered through Celite, concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (15:1)] to give the title compound (700 mg, 25%) as a colourless oil; NMR δH (400 MHz, CDCl3) 8.89 (1H, d, J 5.0 Hz), 8.19 (1H, d, J 2.0 Hz), 7.96 (1H, dd, J 5.0, 2.0 Hz) and 4.66 (2H, s).
Reaction SMILES: C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:6].[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CS(C)=O>[CH:37]1([NH:36][C:35](=[O:6])[NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.0 g (2.5 mmol) diethylenetriamine pentaacetic acid in 50 ml dimethyl sulfoxide (DMSO) was added 1.28 g (6.25 mmol) dicyclohexyl carbodiimide (DCC) and this was stirred for 24 hr at room temperature. During this time the granular solid of DTPA was consumed and the white fluffy solid of dicyclohexyl urea formed. The reaction mixture was filtered and washed with DMSO. The filtrate was split into two equal volumes. The first fraction was concentrated to a thick oil under reduced pressure and heat. A solid precipitated from the oil upon the addition of 30 ml acetonitrile. The solid was collected by filtration, washed with cold acetonitrile and dried under vacuum to give 0.32 g (68%) of a brown solid mp 110°-130° C. NMR analysis revealed an average of one anhydride/DTPA.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)[CH:2]=1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cccnc2)n[nH]1

Procedure:
The title compound was prepared using the method of Example 54 but starting from 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (181 mg; 0.96 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (250 mg; 0.96 mmol). The product precipitated out from DCM during workup and after filtration and drying 110 mg (27%) of pure title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (s, 3H), 4.20-4.60 (m, 3H), 7.05-7.36 (m, 1H), 7.40-7.65 (m, 1H), 7.80-8.60 (m, 7H), 8.85-9.07 (m, 1H), 13.76 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:14][C@H:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:21])=[CH:10][C:11]=2[Cl:20])[NH:6]1)=[O:4].[OH-].[Na+]>CC(C)=O>[C:3]([C@H:5]1[CH2:14][C@H:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:21])=[CH:10][C:11]=2[Cl:20])[NH:6]1)([OH:4])=[O:2]
Reactant: COC(=O)C[C@H]1C[C@H](C(=O)OC)Nc2cc(Cl)cc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)C[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.1 %

Procedure:
Trans-2-methoxycarbonyl-4-methoxycarbonylmethyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (0.4 g, 0.0012 mol) was dissolved in 50% aqueous acetone and cooled to 0° C. whereupon 0.5N sodium hydroxide solution (2.42 ml, 1 molar equivalent) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred for 14 h. The acetone was removed under vacuum and the aqueous residue acidified to pH 1 with 1N hydrochloric acid and extracted into ethyl acetate (2×50 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was purified by chromatography on silica gel using 4% methanol/1% acetic acid in dichloromethane as eluent to give the title compound (0.26 g, m.p. 181°-182° C.) as a colourless solid; δ (250 MHz, CDCl3) 1.72 (1H, ddd, J=13.3, 12.5 and 4.0 Hz, CHACHBHCCHD), 2.36 (1H, dm, J=13.3 Hz, CHACHBHCCHD), 2.39 (1H, dd, J=16.0 and 11.2 Hz, CHEHFCO2CH3), 2.72 (1H, dd, J=16.0 and 3.5 Hz, CHEHFCO2CH3), 3.66 (1H, m, CHACHBHCCHDCH2CH3), 3.73 (3H, s, CO2CH3), 3.99 (1H, dd, J=12.5 and 5.1 Hz, CHACHBHCCHDCH2CO2Me), 515 (1H, br, s, NH), 6.56 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.62 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e 317 (M+); Found C, 49.17; H, 4.13; N, 4.42. C13H13Cl2NO4 requires C, 49.08; H, 4.12; N, 4.40%.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19].C(OC(=O)C)C>CCCCCC>[N+:18](/[CH:21]=[CH:11]/[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])/C=C/c1cccc2ccccc12
Yield: 62 %

Procedure:
7.81 g (50 mmol) of 1-naphthaldehyde and 1.54 g (20 mmol) of ammonium acetate were added to 70 ml of nitromethane and heated under reflux for 3 hours (see: J. Org. Chem., 1984, 49, 4761). 100 ml of ethylacetate was added and the resulting mixture was washed with 50 ml of water and 50 ml of brine. The organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to column chromatography (eluent: hexane/ethylacete=90/10, v/v) to give 6.27 g( 0.031 mmol, Yield 62%) of the title compound.
Reaction SMILES: [CH3:1][NH2:2].O.Br[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>C1COCC1>[CH3:1][NH:2][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CN
Reactant: BrCc1ccc2ccccc2c1
Solvent: O
Solvent: C1CCOC1
Product: CNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a stirred solution of 40 wt % methylamine in H2O (50 mL, 581 mmole) in THF (50 mL) at 0° C. was added 2-(bromomethyl)naphthalene (10 g, 43 mmole) in one portion. The reaction was allowed to warm to RT and stirred for 16 hr, then was then concentrated under vacuum. The residue was taken up in Et2O and washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography on silica gel (98:2 to 9:1 CHCl3/methanol containing 5% NH4OH) gave the tide compound (3.95 g, 54%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 3 H), 7.79 (s, 1 H), 7.49 (m, 3 H), 3.94 (s, 2 H), 2.53 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (502 mg, 3.66 mmol) from Step 2 of Example 70 in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 220 mg, 5.49 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (858 mg, 4.03 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt and stir for a further 3 h. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 30 to 50% ethyl acetate in petroleum ether to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (698 mg, 61%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.41 (s, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.35 (d, J=6.3 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H); LCMS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [OH-].[Na+].O.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11][CH2:10]1)=O)C>C(O)C>[CH2:30]([O:29][C:16]1[CH:17]=[C:18]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:15]=1[CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc(C3CCNCC3)c(OCc3ccccc3)c2)cc1
Yield: 50.4 %

Procedure:
In a 500 ml three-necked flask, 9 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid ethyl ester are dissolved in 180 ml of ethanol, and then 40 ml of a 5M solution of sodium hydroxide are added. The reaction mixture is brought to reflux for 48 hours. The reaction mixture is poured into 400 ml of water. The solid is filtered off and then chromatographed on silica gel (98/2 dichloromethane/methanol). 3.8 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH:19]1O>>[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: CC1CCCC1O
Product: CC1CCCC1OC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and 2-methylcyclopentanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.Br[C:10]1[N:11]=[CH:12][C:13]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:14][C:15]=1[Cl:16]>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:13]1[C:12]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:11][CH:10]=[C:15]([Cl:16])[N:14]=1)(=[O:20])=[O:19]
Reactant: OCc1cccnc1
Reactant: O=S(=O)(Nc1cnc(Br)c(Cl)n1)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1nc(Cl)cnc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyridine-3-methanol (0.22 g) and N-(3-bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.2 g).