Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.CS([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=1)(=O)=O>COCCOC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:27]4[N:28]=[CH:29][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][N:32]=4)[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1O2
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cnc(N2CCN(C3=Nc4ccccc4Oc4ccc(Cl)cc43)CC2)nc1
Yield: 100.2 %

Procedure:
A solution of (E)-2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepine (0.25 g, 0.8 mmol) and ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (0.13 g, 0.57 mmol) in DME was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated aqueous solution of bicarbonate, water, acetic acid and sodium acetate (pH=4), dried over sodium sulfate and solvent evaporated. The resulting crude residue was purified by flash chromatography (0% to 30% ethyl acetate in hexane) to afford title compound 116 (0.265 g, quant.).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:11]1[CH:12]=[C:13]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10]1
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To sodium hydride (0.1 g) taken in a dry 100 ml 3-necked round bottom flask cooled to 0° C., dry dimethylformamide (2 ml) was added. To the above mixture, compound tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g) in DMF (2 ml) was slowly added at 0° C. After 30 min, 2-chloro-N,N-dimethylethylamine (200 mg) in DMF (1 ml) was added to the above mixture. Reaction mixture was allowed to stir at room temperature for overnight, quenched with ice and extracted with ethyl acetate. The organic layer was washed with water (10 ml), brine and dried over sodiumsulphate. The organic layer was filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using 6% Ethyl acetate in hexane as eluant afford tert-butyl 4-(1-(2-(dimethylamino)ethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate as half white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
4-Bromo-3-fluorobenzoic acid, as described above, (40.8 g, 0.187 mol) was dissolved in THF (250 ml) with magnetic stirring under Ar in an ice-H2O bath. The cloudy solution was treated dropwise with borane-THF complex (1 M) (374 mL, 0.374 mol) over a 1 h period maintaining the internal temperature at <10° C. The reaction mixture was left to warm to ambient temperature overnight, then cooled in an ice-H2O bath and treated dropwise with H2O (150 mL). The THF was removed on a rotary evaporator, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL), the organic layers combined, washed with brine, and dried (Na2SO4), filtered, and concentrated to give the title compound as an oil which solidified on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:27]N1C(=O)CCC1=O>CN(C=O)C>[Cl:27][C:17]1[S:16][C:15]([NH:18][C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[N:14][C:13]=1[C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=2)[CH:12]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ncccn4)n3)cn2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ncccn4)sc3Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
According to Scheme 7, Step 1: To a solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (0.85 mmol, 0.31 g) in DMF (1 mL) was added 1-chloropyrrolidine-2,5-dione (0.64 mmol, 85 mg). The reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with a saturated aqueous solution of Na2CO3 and extracted with AcOEt. The combined organic layers were dried over MgSO4, were filtered and were evaporated under reduced pressure to afford 5-chloro-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (0.33 mmol, 130 mg, 38%) as an orange solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[CH3:7][C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>CCO>[CH2:11]([C:10]1[CH:9]=[C:8]([CH3:7])[C:3]([C:1]#[N:2])=[C:4]([SH:5])[N:6]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(=O)CC(C)=O
Reactant: N#CCC(N)=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCc1cc(C)c(C#N)c(S)n1
Temperature: 50 °C
Yield: 64.2 %

Procedure:
To a stirred solution of 2-cyanothioacetamide (1.4 g, 14 mmol) and 2,4-nonanedione (2.0 g, 13 mmol) in anhydrous EtOH (40 mL) was added triethylamine (0.5 mL) and the reaction was heated at 50° C. for 1 h and then was allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH gave 6-pentyl-2-mercapto-4-methyl-nicotinonitrile as a yellow solid (1.84 g, 62.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27]>>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(O)c(OC)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 4-hydroxy-3-methoxybenzaldehyde gave the title compound as a cream solid m.p.:195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(C(=CNC1C=CC(C)=CN=1)C(OCC)=O)#N>>[C:20]([C:14](=[CH:13][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: CCc1ccc(N)nc1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CCOC(=O)C(C#N)=CNc1ccc(C)cn1
Product: CCOC(=O)C(C#N)=CNc1ccc(CC)cn1
Yield: 25.4 %

Procedure:
The title compound (m.p. 155°-156°, 25.4% yield) was prepared from 2-amino-5-ethylpyridine and ethyl ethoxymethylenecyanoacetate in a manner similar to that described for the preparation of ethyl 2-cyano-3-(5-methyl-2-pyridylamino)acrylate in Preparation 6.
Reaction SMILES: [ClH:1].[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[O:19][CH2:20]2)[C@H:15]2[O:29][C@@H:14]32)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3].O>O1CCCC1>[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[O:19][CH2:20]2)[C@H:15]([Cl:1])[C@H:14]3[OH:29])[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Concentrated hydrochloric acid (0.1 ml) was added to a solution of 97 mg of 17α-acetoxy-6α,7α-epoxy-2-oxa-4-pregnene-3,20-dione in 4 ml of tetrahydrofuran, and the solution was stirred at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 102 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([NH2:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]([NH:40][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(C(N)c2ccccc2)cc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 47 %

Procedure:
The title compound was prepared in a yield of 47% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and α-(4-methoxyphenyl)benzylamine.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13]3[C:19]4[C:20]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=6)=[C:27]([Cl:40])[CH:26]=5)=[N:21][CH:22]=[N:23][C:18]=4[S:17][C:14]=32)=[N:9]1)(=O)=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]3[S:17][C:14]4[C:15]5[C:10]([CH2:11][CH2:12][C:13]=4[C:19]=23)=[N:9][N:8]([CH2:7][CH2:6][N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)[CH:16]=5)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To 250 mL CH3CN were sequentially added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]ethyl methanesulfonate (5.80 g, 9.67 mmol), 1-methylpiperazine (3.22 mL, 29.0 mmol), and diisopropylethylamine (3.37 mL, 19.3 mmol). The opaque white suspension was stirred with heating to reflux, upon which the contents turn brown and homogeneous. After 15 h the mixture was removed from heating, and allowed to cool to rt. The contents were concentrated under reduced pressure to 10% volume, diluted with CH2Cl2 (150 mL), and washed with aq NH4Cl (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (50 mL), and the combined organic layers then washed with sat. NaHCO3 (2×100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The solid product was triturated from methanol and then recrystallized from ethanol to afford the final product (3.22 g, 55%) as an off-white solid. 1H-NMR (CD2Cl2) δ 1.98 (s, 3H), 2.30-2.50 (broad m, 8H), 2.68 (t, 2H), 2.98 (t, 2H), 3.25 (t, 2H), 4.08 (t, 2H), 5.07 (s, 2H), 6.93-7.00 (m, 3H), 7.14-7.20 (m, 2H), 7.25-7.39 (m, 2H), 7.75 (s, 1H), 8.31 (s, 1H); LCMS RT=3.15 min; [M+H]+=604.3.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:27]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)[C@@H](C)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (S)-(±)-3-hydroxy-2-methylpropionate (1.06 g, 8.99 mmol) (Aldrich) was dissolved in dichloromethane (10 mL, dried over molecular sieves). Imidazole (0.85 g, 12.41 mmol) (Aldrich) and tert-butyldiphenylsilyl chloride (2.30 mL, 8.85 mmol) (Aldrich) were added and the mixture was stirred at ambient temperature for three hours. The reaction was diluted with additional dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to yield methyl (S)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionate as an oil. (Yield 3.17 g, 98.8%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH3:14][Mg]Br>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)[CH3:14]
Reactant: C[Mg]Br
Reactant: CS(=O)(=O)Nc1cccc(C=O)c1
Solvent: C1CCOC1
Product: CC(O)c1cccc(NS(C)(=O)=O)c1
Reaction time: 2 h

Procedure:
Under argon and at 0° C., 83 mg (0.417 mmol) of N-(3-formylphenyl)methanesulfonamide (Example 86A) were initially charged in 1 ml of abs. tetrahydrofuran. At 0° C., 99 mg (0.833 mmol) of methylmagnesium bromide (3 M in diethyl ether) were added dropwise (resulting in the formulation of a precipitate), and the reaction solution was stirred at this temperature for 2 h. The reaction solution was quenched with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]([F:11])[F:10])=[CH:4][N:3]=1.[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:10][CH:9]([F:11])[C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: Cc1cc(C(F)F)cnc1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C(F)F)cnc1C#N

Procedure:
A solution of 2-chloro-5-difluoromethyl-3-methyl-pyridine (337 mg, 1.898 mmol), Zn(CN)2 (159 mg, 1.328 mmol) and Pd(PPh3)4 (132 mg, 0.114 mmol) in DMF (10 ml) was stirred for 10 min at 120° C. in a microwave, filtered over hyflo and washed with water and brine. The combined aqueous layers were extracted with TBME, the combined organic layers were dried over sodium sulfate, filtered and concentrated. 5-Difluoromethyl-3-methyl-pyridine-2-carbonitrile was obtained as a yellow oil after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 100:0, 3-35 min 100:0 to 80:20). ESI MS: 169 [M+H]; 1H NMR (400 MHz, CDCl3): δ=8.68 (s, 1H), 7.84 (s, 1H), 6.75 (t, 1H), 2.65 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[Cl:14][CH:15]1[CH:20]2[CH:18]3[CH:19]2[CH2:21][CH:16]1[CH:17]3[NH2:22].N1C=CC=CC=1>O>[Cl:14][CH:15]1[CH:20]2[CH:18]3[CH:19]2[CH2:21][CH:16]1[CH:17]3[NH:22][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: NC1C2CC3C1C3C2Cl
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1C2CC3C(C2Cl)C31)c1cnc2ccccc2n1
Yield: 37.1 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 5-chlorotricyclo[2.2.1.0(2,6)]hept-3-ylamine (129 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 100 mg (37%) of (167):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12])[CH3:2].[C:14](Cl)(=[O:16])[CH3:15]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(F)cc1N
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1ccc(F)cc1NC(C)=O
Reaction time: 1 h

Procedure:
A total of 3.84 g of 2-amino-4-fluoro-benzoic acid ethyl ester obtained in Production Example II-7-a was dissolved in 50 ml of pyridine, 1.64 ml of acetyl chloride was added under ice-cooling, and the mixture was stirred for 1 hours. The reaction mixture was diluted with water and was extracted with diethyl ether. The resulting organic layer was washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate, and then evaporated, to give 4.0 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)[N:5]=[C:4]([CH3:24])[N:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)[N:5]=[C:4]([CH3:24])[N:3]=1)=[N+:26]=[N-:27]
Reactant: CCCc1c(Cl)nc(C)nc1Cn1ccnc1-c1cccc(F)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)nc(C)nc1N=[N+]=[N-]

Procedure:
A solution of 124 (2.25 mmol) and NaN3 (731 mg, 11.25 mmol) in DMF (15 ml) is heated at 70° C. in a sealed tube overnight. The solvent is removed in vacuo and water (10 ml) and EtOAc (10 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (2×10 ml). The combined extracts are washed with brine (15 ml) and dried with Na2SO4. The solvent is removed in vacuo and the resulting yellow oil (125) is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C:10]([CH3:12])=[CH2:11].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[C:10](\[CH3:12])/[C:9]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=C(C)C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C(C)=C/c1ccc(N)nc1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a stirred solution of 2-amino-5-bromopyridine (25 g, 140 mmole) in propionitrile (150 mL) was added ethyl methacrylate (50 mL, 400 mmole), DIEA (50 mL, 287 mmole), palladium(II) acetate (1.57 g, 7 mmole), and tri-o-tolylphosphine (4.3 g, 14 mmole). The reaction was purged with argon and heated at reflux for 6 hr, then was cooled to RT and concentrated to dryness under vacuum. The residue was taken up in 80% ethyl acetate/hexanes (100 mL), and the solution was filtered through a pad of silica gel, eluting with 80% ethyl acetatelhexanes (400 mL) until all the product was eluted off. The yellowish filtrate was concentrated under vacuum, and the residue was taken up in a small volume of 1:1 Et2O/petroleum ether. The precipitate which formed was collected and dried under vacuum to give ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (10.77 g, 37%) as a pale yellow solid: LCMS (ES) m/e 207.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.7 Hz,1H), 7.63 (dd,1H), 7.48 (s,1H), 6.75 (d, J=8.8 Hz,1H), 5.79 (br s, 2H), 4.26 (q, 2H), 2.10 (s, 3H), 1.34 (t, 3H). The filtrate was concentrated to dryness and purified by flash chromatography on silica gel (4:1 ethyl acetate/hexanes) to give additional ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (0.87 g, 3%) and ethyl 2-(6-aminopyridin-3-ylmethyl)acrylate (5.77 g, 20%) as a yellow oil: LCMS (ES) m/e 207.0 (M+H)+; 1H NMR (300.MHz, CDCl3) δ 7.86 (d, J=2.1 Hz,1H), 7.32 (dd,1H), 6.53 (d, J=8.5 Hz,1H), 6.21 (d, J=1.8 Hz,1H), 5.48 (d, J=1.4 Hz,1H), 4.17 (q, 2H), 3.47 (s, 2H), 1.27 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH:15]([C:16]([OH:18])=O)[CH2:14][CH:13]=[CH:12][CH2:11]2)=[CH:4][CH:3]=1.Cl.[NH2:20][CH2:21][C:22]#[N:23].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:21]([CH2:22][NH:23][C:16]([CH:15]1[CH:10]([CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:11][CH:12]=[CH:13][CH2:14]1)=[O:18])#[N:20]
Reactant: N#CCN
Reactant: O=C(O)C1CC=CCC1CSc1ccc(F)cc1
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1CC=CCC1CSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 28 h

Procedure:
(1R/S,6R/S)-6-{[(4-Fluorophenyl)sulfanyl]methyl}cyclohex-3-ene-1-carboxylic acid (620 mg, 2.34 mmol) was weighed into a 25 mL round bottom flask and aminoacetonitrile hydrochloride (480 mg, 5.20 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.34 g, 2.60 mmol) were added. Dimethylformamide (8.0 mL) was added and the reaction mixture was cooled to 0° C. After adding triethylamine (1.2 mL, 8.6 mmol) the reaction mixture was stirred at ambient temperature for 28 h, and then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on silica gel with 45:55 ethyl acetate:hexanes eluent provided the title compound as a colorless solid. 1H NMR (500 MHz, acetone-d6): δ=7.92 (1H, br s), 7.41 (2H, dd), 7.08 (2H, dd), 5.64 (2H, m), 4.24 (2H, m), 3.22 (1H, dd), 2.72 (1H, dd), 2.50-2.40 (2H, m), 2.26-2.20 (2H, m), 2.12 (1H, m), 1.86 (1H, m). MS [ESI, (M−H)−] m/z=303.1 amu.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].C[O-].[Na+].CO>>[OH:21][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(-c3ccccn3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccccn3)sc2c1O
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A mixture of 7-hydroxy-2-pyridin-2-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (43 mg, 0.14 mmol) and glycine (214 mg, 2.86 mmol) in 0.5 M sodium methoxide/methanol (5.4 mL, 1.29 mmol) was refluxed for 2 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water and extracted with methyl tert-butyl ether (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (4 mL). The precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (35 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.16 (br s, 1H), 9.47 (br s, 1H), 8.92 (s, 1H), 8.75 (d, J=4.3 Hz, 1H), 8.32 (d, J=7.8, 1H), 8.05 (m, 1H), 7.65 (m, 1H), 4.03 (d, J=6.3 Hz, 2H); MS: (+) m/z 331.00 (M+1); (−) m/z 329.00 (M−1).