Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>[Cu]I>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: Brc1ccccn1
Reactant: C#CCCO
Agent: [Cu]I
Product: OCCC#Cc1ccccn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added 2-bromopyridine (5 g, 31.6 mmol), followed by Pd2Cl2(PPh3)2 (1.11 g, 1.58 mmol) to give a yellow orange suspension. After cooling down to 0° C. under N2, 3-butyn-1-ol (2.28 g, 31.6 mmol) was added. The resulting reaction mixture turned black and it was stirred overnight at 70° C. The reaction mixture was quenched at 0° C. with water, TEA was removed under low pressure, and the organic layer was extracted 3× using DCM, washed with Ammonia, water, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 250 g silicagel column, DCM/MeOH: from 99/1 to 95/5 as eluent) to afford 3.60 g of 4-(pyridin-2-yl)but-3-yn-1-ol as a brown oil (Yield: 77%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([N:11]2[CH2:15][CH2:14][C@H:13]([O:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[Br:24])[CH2:12]2)=[N:9][N:10]=1)=O)C.[NH3:25]>C1COCC1>[Br:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[O:16][C@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[O:7][C:6]([C:4]([NH2:25])=[O:3])=[N:10][N:9]=2)[CH2:12]1
Reactant: N
Reactant: CCOC(=O)c1nnc(N2CC[C@H](Oc3cc(F)ccc3Br)C2)o1
Solvent: C1CCOC1
Product: NC(=O)c1nnc(N2CC[C@H](Oc3cc(F)ccc3Br)C2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl-5-[(3S)-3-(2-bromo-5-fluorophenoxy)pyrrolidin-1-yl]-1,3,4-oxadiazole-2-carboxylate (480 mg, 1.2 mmol) in THF (4 mL) was saturated with ammonia gas for 2 min. The mixture was stirred at room temperature for 0.5 h. The solvent was evaporated and the crude product was dissolved in Et2O, filtered and washed with Et2O to afford the title product as a solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[O:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[O:4]1.[Br:13][CH2:14][CH2:15]Br>O>[CH2:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH2:14][Br:13])=[CH:8][C:6]=2[O:7]1
Reactant: BrCCBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc2c(c1)OCO2

Procedure:
Sodium hydroxide 0.15 g was dissolved in water 6 ml, and Sesamol 0.50 g and 1,2-dibromoethane 0.37 ml were added thereto and heated under reflux for 12 hours. After cooling, water was added thereto, and the product was extracted with ethyl acetate and further washed with brine. The product was dried over magnesium sulfate anhydride and evaporated. The residue was purified by (NH) silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 0.30 g, 34% was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][C@@H:21]([NH:23][CH3:24])[CH3:22])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:25].[C:26]([OH:29])(=O)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][C@@H:21]([N:23]([CH3:24])[C:26](=[O:29])[CH3:27])[CH3:22])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:25]
Reactant: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: CC(=O)O
Product: CC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 27 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 2-chloro-4-[(5-{[(2S)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol (obtained as described in Example 56, preparation of starting materials) to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide in 27% yield; Mass spectrum MH+ 401.3.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[NH2:39][C:40]1[O:44][C:43]([C:45]2[CH:46]=[C:47]([OH:60])[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[N:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:39][C:40]1[O:44][C:43]([C:45]2[CH:50]=[C:49]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:48]=[C:47]([OH:60])[CH:46]=2)=[N:42][N:41]=1
Reactant: CC1(C)OB(c2cc(O)cc(-c3nnc(N)o3)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(-c5nnc(N)o5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 13.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 3-(5-amino-1,3,4-oxadiazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.03 mmol), aqueous solution 2M of sodium carbonate (300 μl, 2.83 mmol) and 5 ml N,N-dimethylformide as a solvent according to the method described in Preparation 186 heating at 100° C. for 48 h. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 40 mg (13% yield) of the title compound. Purity 95%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=399.1, tR (minutes, Method G)=2.57
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11](Cl)=[O:12]>O1CCCC1.O>[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11]([NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)=[O:12]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)Cl
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc([N+](=O)[O-])c1C(=O)Nc1nnn[nH]1
Reaction time: 16 h

Procedure:
To a warm solution of 28 g of 5-aminotetrazole monohydrate in 300 ml of tetrahydrofuran and 15 ml of water was added 26.7 g of 2-methyl-6-nitrobenzoyl chloride in 50 ml of tetrahydrofuran. The solution was allowed to stand for 16 hours, the solvent was evaporated and the residue was treated with water. The solid obtained was separated by filtration, slurried with ether and again separated by filtration to give 2-methyl-6-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 230°-232° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])=[C:9]([F:20])[C:8](=[O:21])[NH:7][CH:6]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>CO>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7][C:8](=[O:21])[C:9]=2[F:20])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1c[nH]c(=O)c(F)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c[nH]c(=O)c(F)c1Nc1ccc(Br)cc1F
Reaction time: 8 h
Yield: 99 %

Procedure:
A stirred solution of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.10 g, 0.278 mmol) in 4:1 THF:MeOH (5 mL) was treated with 1 M LiOH solution (0.75 mL). After 8 hours, the reaction mixture was acidified to pH 1 with 1 N HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give 0.095 g (99%) of desired product as a white solid. MS APCI (−) m/z 343, 345 (M−, Br pattern) detected; 1H NMR (400 mHz, DMSO) δ 12.34 (bs, 1H), 9.39 (bs, 1H), 7.95 (s, 1H), 7.59 (d, 1H), 7.36 (d, 1H), 7.12 (td, 1H).
Reaction SMILES: NC1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:24][N:25]([CH:27]=O)[CH3:26]>>[CH3:26][N:25]([CH3:24])[C:27]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH:6]=1
Reactant: CC(=O)c1cc(N)cn1Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)c1cc(N(C)C)cn1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a 100 mL round bottomed flask with a stirring bar and a nitrogen inlet was added 1-[4-amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1 (0.50 g, 2.15 mmol), dry DMF (20 mL), finely powdered Cs2CO3 (3.26 g, 10 mmol) and Mel (0.31 mL, 5.00 mmol). The resulting mixture was stirred lh at ambient temperature. The solids were removed by filtration and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with water (3×) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 50% EtOAc-hexanes as eluant to give 1-[4-dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-3-1 as an oil. 1H NMR (CDCl3) δ 2.36 (3H, s), 2.70 (6H, s), 5.46 (2H, s), 6.36 (1H, d, j=2.0 Hz), 6.50 (1H, d, j=2.0 Hz), 6.98 (2H, m), 7.11 (2H, m).
Reaction SMILES: [I-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:29][CH:26]4[CH2:28][CH2:27]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1
Reactant: NC1CC1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-bromo-1-[(cyclopropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:8](C=O)=[CH:9][CH:10]=1)=[O:4].[C:23](O)(=O)[CH2:24][C:25]([OH:27])=[O:26].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:8]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:9][CH:10]=1)=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)c1ccc(C=O)c(-c2cccc(C(F)(F)F)c2)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C=CC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The compound of step 3 of example 428 (400 mg, 1.30 mmol), malonic acid (262 mg, 2.52 mmol) and piperidine (16 mg, 0.19 mmol) were dissolved in pyridine (0.7 ml) and stirred in reflux for 1 h. The material was partitioned between 2N hydrochloric acid and ethyl acetate (product is only sparingly soluble). The combined organic extracts were dried over sodium chloride and evaporated to dryness to yield the title compound.
Reaction SMILES: [F:1][C:2]1([F:59])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42](O)[CH:43]([CH3:45])[CH3:44])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:47]([F:58])[C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:59][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][CH:43]([CH3:44])[CH3:45])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:47]([F:58])[C:48]2[CH:49]=[CH:50][C:51]([C:54]([F:55])([F:57])[F:56])=[CH:52][CH:53]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(O)C(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 41 h
Yield: 27.3 %

Procedure:
To a solution of 70 mg (0.085 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(1-hydroxy-2-methylpropyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 19, in 5 ml of dichloromethane, 2 ml of triethyl silane and 1 ml of trifluoroacetic acid were added, and the reaction solution was stirred at room temperature for 41 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-85/15 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 16 mg of the title compound as a white solid (yield: 27%).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1.O.[NH2:25][NH2:26]>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:26][N:25]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Reactant: NN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n[nH]1
Reaction time: 24 h

Procedure:
In a further embodiment, a pyrazole cyclization reaction is provided in Scheme 14A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The pyrazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydrazine hydrate to provide ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol and glacial acetic acid for about 2 to 16 hours. Ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate is then reduced with lithium aluminum hydride to provide 3-(4-fluorophenyl)-1H-pyrazol-5-yl-methanol. In one embodiment, the reduction is performed in THF at a temperature of about 0° C. to about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde is then formed by oxidizing 3-(4-fluorophenyl)-1H-pyrazole-5-methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:18]=2)[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:19][O:20][C:21]([C:23]1([NH2:31])[CH2:28][CH2:27][CH:26]([CH2:29][CH3:30])[CH2:25][CH2:24]1)=[O:22]>>[CH3:19][O:20][C:21]([C:23]1([NH:31][C:15]([C:14]2[CH:13]=[N:12][CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=3)[CH:18]=2)=[O:17])[CH2:28][CH2:27][CH:26]([CH2:29][CH3:30])[CH2:25][CH2:24]1)=[O:22]
Reactant: CCC1CCC(N)(C(=O)OC)CC1
Reactant: COc1ccc(-c2cncc(C(=O)O)c2)cc1Cl
Product: CCC1CCC(NC(=O)c2cncc(-c3ccc(OC)c(Cl)c3)c2)(C(=O)OC)CC1

Procedure:
The title compound was synthesized from 5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid and 1-Amino-4-ethyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[N:13]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 25.3 %

Procedure:
The title compound (0.03 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-bromomethyl-benzoic acid methyl ester (0.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C22H22ClN3O2, 395.14. found, m/z 396.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.63-7.19 (m, 7H), 7.03-7.02 (m, 2H), 5.27 (s, 2H), 3.15 (s, 2H), 2.79-2.67 (m, 8H).
Reaction SMILES: [CH:1]12[CH2:9][C:8](=[O:10])[O:7][CH:6]1[CH2:5][CH2:4][CH:3]=[CH:2]2.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(Cl)Cl>[CH:1]12[CH2:9][CH:8]([OH:10])[O:7][CH:6]1[CH2:5][CH2:4][CH:3]=[CH:2]2
Reactant: O=C1CC2C=CCCC2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OC1CC2C=CCCC2O1
Yield: 87.8 %

Procedure:
A solution of 13.8 g of 7-oxabicyclo[4.3.0]non-2-en-8-one, prepared by following the procedures of E. J. Corey and T. Ravindranathan, Tetrahedron Letters, 4753 (1971), in 100 ml of dry methylene chloride (passed through Woelm activity grade I alumina prior to use) was stirred at -78° C. under argon as 19.0 ml (107 mmol) of diisobutylaluminum hydride was added dropwise over 0.5 hour. After 3 hours at -78° C. the reaction mixture was quenched at -78° C. by the slow addition of several ml of 10% aqueous hydrochloric acid. The resultant mixture was then stirred in an ice-water bath as 100 ml of 10% hydrochloric acid was added dropwise. The layers which formed were separated and the aqueous phase was extracted twice more with methylene chloride. The combined methylene chloride extracts were washed with brine and then with saturated aqueous sodium bicarbonate. The washed extract was dried (Na2SO4) and evaporated in vacuo to yield 12.3 g of 7-oxabicyclo[4.3.0]non-2-en-8-ol: ir (CHCl3) 14.3, 13.7, 10.87, 9.90, 9.61, 9.27, 6.90, 3.40, and 2.78 to 3.13μ (broad); nmr δ 1.0-3.0 (m, 7H), 4.0-4.8 (m, 2H) and 5.2-6.0 (m, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9](Cl)(=[O:11])=[O:10])=[N:7][CH:8]=1.[NH2:13][CH2:14][CH2:15][OH:16].CCN(CC)CC>C(#N)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:13][CH2:14][CH2:15][OH:16])(=[O:11])=[O:10])=[N:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Reactant: NCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(NCCO)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial equipped with a magnetic stir bar were combined 5-bromopyridine-2-sulfonyl chloride hydrochloride (50 mg, 0.171 mmol), 2-aminoethanol (0.015 mL, 0.256 mmol), Et3N (0.071 mL, 0.512 mmol), and acetonitrile (1 mL). The resulting yellow solution stirred at room temperature overnight. The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (15 mL). The combined organic layers were concentrated to give the title compound as a clear liquid, which was used without further purification (55 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[C:22]([S:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1F>>[Cl:17][C:18]1[CH:23]=[C:22]([S:24]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C(=O)O)c1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(Cc1ccc(F)cc1)c1ccc(F)c(Cl)c1
Product: CC(C(=O)O)c1cc(Oc2ccc(S(=O)(=O)Cc3ccc(F)cc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 50 step (iii) and the product from example 34 step (i).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[N:12][C:5]=2[NH:4][C:3]1=[S:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][S:13][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][CH:11]=[N:12][C:5]=4[N:4]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=S)[nH]c2ncccc2c1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2ncccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a solution of 3-methylpyrido[2,3-d]pyrimidin-4-one-2-thione (193 mg) in DMF (5 ml) were added sodium hydride (60 mg) and 4-(4-chlorobenzoyl)benzyl bromide (310 mg) and the mixture was stirred at room temperature for 30 minutes. The reaction mixtrue was then diluted with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was then distilled off. The residue was recrystallized (ethyl acetate-ether-hexane) to provide the title compound as white powder (162 mg, 38%). 1H-NMR (CDCl3) δ: 3.62(3H,s), 4.73(2H,s), 7.26-7.79(9H,m), 8.54-8.61(1H,m), 8.90-8.95(1H,m).