Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:11]=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[N:38]=[C:39]=[O:40]>O1CCCC1.CCCCCC>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:39](=[O:40])[CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:11]=[N:10][N:9]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCCCn1nnnc1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nnnc1C(C(=O)Nc1ccc(F)cc1F)c1ccccc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
The compound from (a) above (1.5 g; 4.5 mmoles) was dissolved in tetrahydrofuran (20 mL), cooled to -20° C., and then treated dropwise with n-butyllithium (2.8 mL; 4.5 mmoles) for over 5 minutes. The solution was stirred for 5 minutes before adding 2,4-difluorophenyl isocyanate (0.7 g; 4.5 mmoles). The ice bath was removed and the solution gradually warmed to room temperature over 30 minutes, at which time the reaction was quenched with water (20 mL) and diluted with ethyl acetate. The layers were separated and the organic portion was washed with aqueous HCl (1N), aqueous sodium carbonate (10%), and brine. The solution was dried over magnesium sulfate, filtered, and stripped to dryness leaving a viscous liquid that was dissolved in 75% hexane/25% ethyl acetate and chromatographed using silica gel. Yield: 0.9 g (41%).
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].C[CH:11]1[CH2:16][CH:15]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][N:18]=2)[CH2:14][CH2:13][NH:12]1>C(Cl)(Cl)Cl>[C:2]([N:12]1[CH2:11][CH2:16][CH:15]([C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][N:18]=2)[CH2:14][CH2:13]1)#[N:1]
Reactant: CC1CC(c2nsc3ccccc23)CCN1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nsc3ccccc23)CC1
Yield: 39.1 %

Procedure:
To a stirred mixture of 5.9 g of cyanogen bromide, 8.6 g of potassium carbonate, and 80 ml of chloroform was added, dropwise, 11.0 g of 3-(2-methyl-4-piperidinyl)-1,2-benzisothiazole, in 30 ml of chloroform. The mixture was stirred under reflux for 4 hrs, cooled, filtered and the filtrate was concentrated in vacuo to a solid. The solid was triturated with hexane and recrystallized from methanol-water (twice) to yield 4.5 g (36%) of product, mp 118°-120°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: Fc1ccccn1
Reactant: O=Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1cccn1-c1ccccn1
Temperature: 120 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
A mixture of 10 g of 2-pyrrolecarbaldehyde, 10 g of 2-fluoropyridine, 24 g of cesium carbonate and 100 ml of N-methylpyrrolidone was stirred at 120° C. for 1 day. The reaction mixture was allowed to cool to room temperature. Water was poured into the mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 7.7 g of 1-(2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:14])(=[O:13])[NH:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[C:23]([O:31][CH3:32])[CH:22]=2)[N:16]=1.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:13])(=[O:14])[NH:9][CH:10]2[CH2:11][CH2:12]2)=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=3)=[O:27])=[C:23]([O:31][CH3:32])[CH:22]=2)[N:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(S(=O)(=O)NC4CC4)ccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3cc(S(=O)(=O)NC4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-5-(N-cyclopropylsulfamoyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-40, 0.040 g, 0.08 mmol), 3-(trifluoromethyl)aniline (0.020 g, 0.12 mmol), trimethyl aluminium (2M solution in toluene) (1 ml) and dry toluene (5.0 mL) to afford 0.015 g of crude product, which was purified by washing with methanol:DCM:DEE to afford 0.015 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 0.42 (s, 2H), 0.54 (d, J=5.4 Hz, 2H), 2.20 (m, 1H), 3.96 (s, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.61 (t, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.80-7.84 (m, 2H), 7.96 (s, 3H), 8.18 (m, 2H), 8.26 (s, 1H), 10.40 (s, 1H), 12.88 (br s, 1H); MS (m/z): 606.13 (M−H)−.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:34]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=3[NH:32][C:31](=O)[C@H:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:29]=2)=[CH:24][CH:23]=1>ClCCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:34]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=3[NH:32][C:31](=[S:2])[C@H:30]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:29]=2)=[CH:24][CH:23]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=S
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A suspension of P4S10 (36.1 g, 81.1 mmol) and Na2CO3 (8.6 g, 81.1 mmol) in 1,2-DCE (700 ml) at room temperature was stirred for 2 h before methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]acetate (for a preparation see Reference compound D) (16.8 g, 45.1 mmol) was added. The resulting mixture was stirred at 70° C. for 2 h before being cooled and filtered. The solid was washed twice with DCM and the filtrate washed with sat. Sodium hydrogen carbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash-chromatography on silica gel (DOM/MeOH: 99/1) to afford the title compound (17.2 g, 98% yield) as a yellowish solid. LC/MS (Method D): m/z 389 [M(35Cl)+H]+, Rt 2.64 min
Reaction SMILES: N1CCCCC1.[CH:7]1([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH:7]1([O:12][C:13]2[CH:20]=[CH:19][C:16](/[CH:17]=[CH:26]/[C:27]([NH:29][C:30]3[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=3[C:32]([OH:34])=[O:33])=[O:28])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cc(C=O)ccc1OC1CCCC1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC1CCCC1
Yield: 67.8 %

Procedure:
Piperidine (0.45 mL, 4.5 mmol) was added to a suspension of 4-cyclopentyloxy-3-methoxybenzaldehyde (1.0 g, 4.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.92 g, 4.1 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-{[3-(4-cyclopentyloxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (1.06 g, 67%) as a pale yellow crystalline solid; mp 96-98° C.; δH (400 MHz, DMSO-d6) 1.46 (m, 2H, CH2), 1.67-1.71 (m, 4H, CH2), 1.90 (m, 2H, CH2), 3.81 (s, 3H, OCH3), 4.82 (t, J=5.6 Hz, 1H, OCH), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 6.94 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.19 (dd, J5′,6′=8.4, J5′,6′=1.6 Hz, 1H, H6′), 7.35 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.54 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 HZ, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 23.7, 32.3, 55.7, 79.5, 110.9, 114.0, 116.5, 119.7, 120.3, 122.5, 122.6, 127.0, 131.1, 134.0, 141.1, 141.7, 149.0, 149.6, 164.2, 169.5; HRMS (ESI) calculated for C22H23NO5 [M+Na]+ 404.1468. found 404.1468; vmax 747, 1261, 1506, 1584, 1659, 2964, 3524 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([CH:17]([OH:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Li+].I[CH2:38][CH3:39]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([CH:17]([O:24][CH2:38][CH3:39])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)c3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CCI
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCOC(c1ccccc1)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-(hydroxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (276 mg, 0.585 mmol) in NMP (3 mL) was added lithium hydroxide (28.0 mg, 1.170 mmol) and iodoethane (142 μL, 1.754 mmol), and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with sat. aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/0-50% EtOAc) to afford racemic 4-(5-chloropyridin-3-yl)-2-(ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak OJ-H, 21×250 mm, MeOH in CO2) to afford 4-(5-chloropyridin-3-yl)-2-((R)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 4-(5-chloropyridin-3-yl)-2-(S)-ethoxy(phenyl)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C29H30ClN5O [M+H]+ 500. found 500. 1H NMR (600 MHz, CD3OD) δ 8.75 (d, J=2.3, 1H), 8.70 (d, J=1.6, 1H), 8.27 (s, 1H), 8.23 (t, J=2.0, 1H), 7.49 (d, J=7.2, 2H), 7.38 (t, J=7.3, 2H), 7.36-7.31 (m, 1H), 5.94 (s, 1H), 4.01-3.85 (m, 2H), 3.68-3.59 (m, 2H), 1.44-1.36 (m, 2H), 1.27 (t, J=7.0, 3H), 1.07-0.98 (m, 1H), 0.89-0.78 (m, 1H), 0.76-0.66 (m, 5H), 0.64-0.54 (m, 1H), 0.54-0.46 (m, 1H), 0.46-0.36 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[NH:3]1.Cl[C:14]([O:16][C:17]([CH3:19])=[CH2:18])=[O:15]>N1C=CC=CC=1>[C:17]([O:16][C:14]([N:3]1[C:4]2[C:9](=[CH:8][N:7]=[CH:6][CH:5]=2)[NH:10][C:11](=[O:12])[CH:2]1[CH3:1])=[O:15])([CH3:19])=[CH2:18]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC1Nc2ccncc2NC1=O
Solvent: c1ccncc1
Product: C=C(C)OC(=O)N1c2ccncc2NC(=O)C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
(2RS)-2-Methyl-1,2-dihydro-1,4,6-triazanaphthalen-3(4H)-one (A. Albert, G. B. Barlin J. Chem. Soc. 1963, 5156) (570 mg, 3.5 mmol) was dissolved in 30 ml of anhydrous pyridine and cooled in an ice bath. 0.42 ml (3.8 mmol) of isopropenyl chloroformate was added dropwise, and the mixture was subsequently stirred at room temperature overnight. Concentration, chromatography on silica gel (ethyl acetate/methanol=20:1) and crystallization (pentane/diethyl ether) resulted in 100 mg (12%) of the desired product of melting point 170°-171° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[C:23]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)[CH:22]=2)=[O:19])=[CH:37][C:38]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The intermediate compound 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide was made as for Example 24 (Step 1 to 2) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 10.78 (1H, s), 8.55 (1H, d, J=2.1 Hz), 8.26 (1H, s), 8.22 (1H, s), 8.11 (1H, s), 7.99-8.03 (1H, dd, J=2.1 and 8.1 Hz), 7.76-7.80 (2H, m), 7.49 (1H, s), 2.19 (3H, s). LCMS: m/z [M+H]+ 505.9663.
Reaction SMILES: I[CH3:2].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16](=[O:18])[CH3:17])[CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[C:19](=[O:21])[CH3:20].[OH-].[K+]>C1COCC1>[CH3:2][N:14]1[C:13]2[CH:12]=[C:11]([C:16](=[O:18])[CH3:17])[CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][C:4]([C:19](=[O:21])[CH3:20])=[CH:5][CH:6]=2
Reactant: CI
Reactant: CC(=O)c1ccc2c(c1)[nH]c1cc(C(C)=O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c3ccc(C(C)=O)cc3n(C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.747 mL, 11.94 mmol) was added to the mixture of 1,1′-(9H-carbazole-2,7-diyl)diethanone (1 g, 3.98 mmol) and potassium hydroxide (0.223 g, 3.98 mmol) in THF (20 mL) and stirred for overnight at room temperature. The solvent was then removed under reduced pressure and the crude was extracted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated to get the pure product as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([N:18]1[CH2:17][CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]1)(=[O:26])[CH3:25]
Reactant: O=C(O)C1(c2ccccc2Sc2ccc(F)cc2)CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccc(F)cc2)CC1

Procedure:
A mixture of 0.7 g of 4-[2-(4-fluorophenylthio)phenyl]piperidine-4-carboxylic acid and 0.83 ml of acetic anhydride in 4.2 ml of pyridine is stirred at reflux for 4 hours. Thereafter, the excess pyridine is removed by rotary evaporation and the residue is taken up in 10 ml of water, where it is treated with 10 ml of 1 N hydrochloric acid. The acidic mixture is extracted thrice with 20 ml portions of an ether-benzene (1:1) mixture and the combined extracts are successively washed twice with 40 ml portions of water, washed once with a 15 ml portion of a saturated sodium chloride solution and dried. The resulting residue is recrystallized from an acetone-ether (1:4) mixture providing 1-acetyl-4-[2-(4-fluorophenylthio)phenyl]piperidine-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH-].[K+].[CH:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>CS(C)=O>[CH:13]1([O:19][C:2]2[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OC1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OC2CCCCC2)nc1
Reaction time: 21 h
Yield: 55.5 %

Procedure:
6-Chloronicotinic acid (0.500 g, 3.17 mmol), powdered potassium hydroxide (0.712 g, 12.69 mmol) and cyclohexanol (0.636 g, 6.35 mmol) were combined in DMSO (12 mL) and heated in a sealed tube to 100 C for 18 h and then to 120 C for 21 h. The mixture was acidified to pH 1 by adding 2M hydrochloric acid. The mixture was then left to stand at room temperature overnight and the resultant precipitate filtered off, washed with water and dried under vacuum to afford the title compound as a cream solid (0.389 g, 55%). 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.76 (1H, d), 8.19 (1H, dd), 6.79 (1H, d), 5.11 (1H, m), 2.03 (2H, m), 1.83 (2H, m), 1.64 (1H, m), 1.56 (2H, m), 1.47 (2H, m) and 1.38 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.[C:15]1([S:21]([N:24]([CH2:28][CH2:29]Cl)[CH2:25][CH2:26]Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CCCC)CCCC)CCC>CO>[C:15]1([S:21]([N:24]2[CH2:28][CH2:29][N:1]([C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=4[CH:14]=3)[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: O=S(=O)(c1ccccc1)N(CCCl)CCCl
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: COC(=O)c1cc2cc(N3CCN(S(=O)(=O)c4ccccc4)CC3)ccc2o1
Temperature: 75 °C
Reaction time: 43 h
Yield: 53.6 %

Procedure:
Methyl 5-aminobenzofuran-2-carboxylate (200 g) and N-benzenesulfonyl-N,N-bis(2-chloroethyl)amine (289 g) were added to tributyl amine (1012 ml) under stifling at 25-30° C. The resulting mixture was heated to 73-77° C., followed by stirring for 43 hours at the same temperature. The reaction mass was cooled to 25-30° C., followed by the addition of methanol (506 ml) and then stirring for 30 minutes at 25-30° C. The resulting mass was filtered, washed with chilled methanol (200 ml) and then dried to produce 220 g of methyl 5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate as a fine powder (Purity by HPLC: 99.5%).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11].[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>O>[O:6]([C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[O:11])[Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26]
Reactant: O=C(OCC(F)(F)F)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCC(F)(F)F)c1
Reaction time: 10 h

Procedure:
Into a 250 mL round bottom flask was added 30 mL of dry dimethyl formamide and 4.0 parts of ester (47) and 3.5 parts of tert-butyldimethyl silyl chloride were added to the reaction flask with stirring. Three parts of Imidazole was added in portions and stirring was continued for 10 hours. The reaction mixture was diluted with 80 mL of water and the product was extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an oil, yield 5.65 parts. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32](I)=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:32]([C:49]4[C:48]([CH3:61])=[N:47][N:46]([CH2:45][C:44]5[CH:62]=[CH:63][CH:64]=[C:42]([F:41])[CH:43]=5)[C:50]=4[CH3:51])=[CH:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:24]3=[N:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc3c(I)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cccc(F)c5)c4C)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 25.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-6-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 33) (200 mg, 0.31 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (123.15 mg, 0.37 mmol) in sodiumcarbonate (98.57 mg, 0.93 mmol), Pd(PPh3)2Cl2 (10.8 mg, 0.01 mmol), 1,2-dimethoxyethane/water (10/2 ml) to give 60 mg (25.4% yield) of titled compound. MS: m/z=760.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Br:17]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 1.058 mmol)[prepared in Example 99] and N-bromosuccinimide (188 mg, 1.06 mmol) in tetrahydrofuran (5.29 ml) was stirred in a sealed tube for 1 h at 70° C. Sodium hydroxide (3.53 ml, 21.16 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (289 mg, 0.96 mmol, 91% yield) as a yellow oil: LCMS (ES) m/e 301, 303 (M, M+2)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:16][C:17]1[N:22]2[N:23]=[C:24](/[CH:26]=[CH:7]/[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)[N:5]=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1
Reactant: Cn1nc(N2CCCCC2)nc1C=O
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc(C)n2nc(/C=C/c3nc(N4CCCCC4)nn3C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 1-methyl-3-(piperidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (60 mg, 309 μmol, Eq: 1.00), ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (142 mg, 309 μmol, Eq: 1.00) and DBU (51.7 mg, 51.2 μl, 340 μmol, Eq: 1.1) in tetrahydrofuran (15 ml) was stirred for 18 hours at 25° C. under argon. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate/methanol 0-7% as eluent affording 5,8-dimethyl-2-[(E)-2-(2-methyl-5-piperidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-[1,2,4]triazolo[1,5-a]pyrazine (56 mg, 53.6%) as a yellow solid. MS: m/z=339.5 (M+H+), MP: 186-188° C.