Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[N:2].[ClH:20]>O1CCOCC1>[ClH:20].[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1([C:1]#[N:2])[CH2:4][NH:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(c2ccccn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2ccccn2)CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A sample of tert-butyl 3-cyano-3-pyridin-2-ylazetidine-1-carboxylate (I-2, 485 mg, 1.9 mmol) was treated with HCl (20 mL of a 4.0 M solution in dioxane) and stirred at room temperature for 2 h before being concentrated under reduced pressure to afford 3-pyridin-2-ylazetidine-3-carbonitrile hydrochloride (365 mg, 99%) which was used without further purification.
Reaction SMILES: C([NH:8][C@@H:9]1[C@@H:13]([F:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:8][C@@H:9]1[C@@H:13]([F:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](F)C1
Yield: 99.2 %

Procedure:
(3S,4S)-tert-butyl 3-(benzylamino)-4-fluoropyrrolidine-1-carboxylate, 82 (24 mg, 0.082 mmol) was subjected to hydrogenolysis with 10 wt % Pd—C(10 mg) in ethanol (3 ml). The reaction mixture was filtered, concentrated and azeotroped dry with CHCl3 to provide (3S,4S)-tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate (16.6 mg, 0.081 mmol, 99.2% yield) that was used in the next step without purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][Mg]Br>O1CCCC1>[OH:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (4-oxocyclohexyl)methylcarbamate (1.00 g) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Methylmagnesium bromide (4.40 mL) was added dropwise. The reaction was stirred for 2 hours at −78° C. then allowed to warm to 0° C. and stirred for 30 minutes. The resulting suspension was quenched with water (10 mL), diluted with ether (50 mL), washed with ammonium chloride (25 mL), washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 80 g) eluting using a gradient of 5% to 50% ethyl acetate/dichloromethane over 30 minutes (flow=60 mL/min) gave the title compound as a 2:1 mixture of cis and trans isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2.[N:25]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:32](=[O:33])[CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CN4CCOCC4)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine and morpholin-4-yl-acetic acid; MS: m/e=447.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([O:22]CC)=[O:21])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[CH:25]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(OCC)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reaction time: 20 h
Yield: 92.5 %

Procedure:
To a solution of ethyl 7-(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (447.8 mg) in ethanol (20 ml) was added 2N sodium hydroxide (2.0 ml) at room temperature, and the mixture was stirred for 20 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate and concentrated. The resulting crystal was collected by filtration to give 7-(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (380 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:42][CH2:41]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4F)noc3C)CC2)c1
Yield: 85.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (622 mg, 1.57 mmol, 86%) was obtained.
Reaction SMILES: [CH:1]([C:4]1([C:29]#[N:30])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:10]=2)[C:5]1=[O:28])([CH3:3])[CH3:2].C(=O)=O.CO.C(#N)C>>[CH:1]([C@@:4]1([C:29]#[N:30])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:20][CH:21]=3)[N:10]=2)[C:5]1=[O:28])([CH3:3])[CH3:2]
Reactant: CC(C)C1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Agent: O=C=O
Solvent: CO
Solvent: CC#N
Product: CC(C)[C@@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Yield: 15.3 %

Procedure:
3-Isopropyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (85 mg) obtained in Example 5 was resolved by SFC (column: CHIRALCEL OJH, 20 mmID×250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide/methanol/acetonitrile=660/170/170), and the compound having a shorter retention time was recrystallized (hexane/ethyl acetate) to give the title compound (13 mg).
Reaction SMILES: [Mg].[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].[C:18](=[O:20])=[O:19].Cl>O1CCCC1>[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: O=C=O
Reactant: CCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1

Procedure:
A Grignard reagent was prepared from a solution of 50 ml of dried tetrahydrofuran in which 0.88 g (36.7 mmol) of magnesium and 10.0 g (35.6 mmol) of 1-(trans-4-n-propylcyclohexyl)-4-bromobenzene were dissolved, and the Grignard reagent was put into dry ice. After vaporizing the dry ice, hydrochloric acid was added to the resultant to give a precipitate, and the precipitate was filtered, washed with water, dried, and recrystallized from toluene to give 7.5 g (30.5 mmol) of p-(trans-4-propylcyclohexyl)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]1=[S:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cccc3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cccc3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1=S
Temperature: 80 °C

Procedure:
A mixture of (R)-3-(tert-butoxycarbonylamino)-1-[7-(tert-butyl-dimethylsilyloxy)naphthalen-1-yl]-2-oxopyrrolidine, as described above in Step F, (113 mg, 0.247 mmol) and Lawesson's Reagent (50 mg, 0.124 mmol) in dry toluene (0.5 mL), under argon, was heated to 80° C. for 1 hour. The reaction mixture was allowed to cool, then poured directly onto a silica gel column and chromatographed, eluting with a gradient of hexane—5% to 25% EtOAc to yield the titled product as a clear oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[C:25]2[C:21](=[CH:22][N:23]([CH3:26])[N:24]=2)[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:26][N:23]1[CH:22]=[C:21]2[C:25]([C:17]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:18][C:19]([N+:27]([O-:29])=[O:28])=[CH:20]2)=[N:24]1
Reactant: OB(O)c1ccccc1
Reactant: Cn1cc2cc([N+](=O)[O-])cc(Br)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc2cc([N+](=O)[O-])cc(-c3ccccc3)c2n1

Procedure:
Phenylboronic acid (244 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1, 40 mg), dioxane (4 mL), a 2 M aqueous sodium carbonate solution (1 mL), and the reaction solution were added to 7-bromo-2-methyl-5-nitro-2H-indazole obtained in the above-described Step 1 (256 mg). The reaction solution was allowed to react in a microwave reactor at 130° C. for 1 hour. The solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-methyl-5-nitro-7-phenyl-2H-indazole.
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH:20]([CH3:29])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:20]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:29])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(=O)c1ccccc1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 1516.1 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (7.73 g, 26.3 mmol), 2-bromo-1-phenylpropan-1-one (5.94 ml, 39 mmol) and K2CO3 (12.7 g, 92 mol) was treated according to general preparation 2, then recrystallized with ethanol to give 85 g of N1-(4-nitrobenzyl)-N4-(1-benzoylethyl)piperazine dihydrochloride, yield 70%, mp 256-8° C., which was reduced by reductive iron in the similar procedure of Example 12, to give compound (IV-13), yield 65%, mp 244-246° C. (dec). M+ 323.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]1[O:16][CH:13]1[CH2:14][CH3:15].C(C1CCCCC1O)(C)(C)C.C1OC1C>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3].[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC1CO1
Agent: CC(C)(C)C1CCC(O)CC1
Agent: CC(C)(C)C1CCCCC1O
Agent: CC1CO1
Product: CCC(O)COC1CCC(C(C)(C)C)CC1

Procedure:
The synthesis was carried out in the same manner as described in Example 1, except that 30.0 g (0.192 mol) of 4-tert-butylcyclohexanol (cis:trans=8:2) and 13.8 g (0.192 mol) of 1,2-butyleneoxide were used instead of 30.0 g (0.192 mol) of 2-tert-butylcyclohexanol (cis:trans=8:2) and 11.1 g (0.192 mol) of propyleneoxide. 9.6 g of 4-tert-butylcyclohexanol and 17.9 g of 1-(4-tert-butylcyclohexyloxy)-2-butanol (cis:trans=8:2) (bp. 130° to 133° C./5 mm Hg) were obtained in a 41% yield. Then, the cis-trans isomers of 1-(4-tert-butylcyclohexyloxy)-2-butanol were separated from each other in the same manner as described in Example 1.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].C(N(C(C)C)CC)(C)C.O([CH2:42][CH:43]([F:45])[F:44])S(C(F)(F)F)(=O)=O>C1COCC1>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:42][CH:43]([F:45])[F:44])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CC(F)F)CC1
Reaction time: 24 h

Procedure:
To a suspension of (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride (0.13 mmole) from experiment K4 in THF (2 ml) was added at 22° C. diisopropyl ethyl amine (0.75 mmole) and 2,2-difluoroethyl triflate (0.60 mmole) and stirring was continued at 60° C. for 24 h. The mixture was quenched with methanol, acidified with acetic acid and subjected to prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2,2-difluoro-ethyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 418.2 [M+H]+.
Reaction SMILES: [N+:1]([CH:4]([CH3:8])[CH:5]([OH:7])[CH3:6])([O-:3])=[O:2].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O>[N+:1]([CH:4]([CH3:8])[CH:5]([O:7][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:6])([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(C)[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.3 %

Procedure:
2.4 g (20 mmol) of 3-nitro-2-butanol was dissolved in 10 ml of dimethylformamide, 4.08 g (60 mmol) of imidazole and 4.52 g (30 mmol) of tert-butyldimethylsilyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 6 hours. After the reaction, the reaction solution was poured into 100 ml of ice water, and the mixture was extracted with diethyl ether. The organic layer was washed successively with 2N hydrochloric acid, saturated sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane-benzene=10:1) to give 4.73 g of 3-nitro-2-(tert-butyldimethylsilyloxy)butane as a colorless oil (yield: quantitative).
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[F:28].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]2[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=2)=[CH:23][C:22]=1[F:28]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(Cl)c(F)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 33 mg, 0.092 mmol) in DMSO (1 mL) was added 4-chloro-3-fluorophenol (13.5 mg, 0.092 mmol) and K2CO3 (25 mg, 0.18 mmol). The reaction was stirred at room temperature for 3 hours and then at 40° C. for 16 hours. After 16 hours the reaction was diluted with DCM (10 mL) and water (20 mL). The organic was separated and the aqueous was extracted with DCM (2×10 mL). The combined organics were filtered through a phase separation cartridge and reduced to dryness to give a yellow oil which was purified by reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)#[N:3]>O1CCOCC1>[C:2]([C:4]1[CH:5]=[C:6]([S:10]([NH2:1])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)#[N:3]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: N
Solvent: C1COCCO1
Product: N#Cc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of ammonia in dioxane (0.5 M in dioxane; 50 mL; 25 mmol) was added a solution of 3-cyanobenzene-1-sulfonyl chloride (ABCR; 605 mg; 3 mmol) in dioxane (10 mL) and the mixture was allowed to stir at RT for 30 min. The solvent was removed in vacuo to give the title compound as a white solid (450 mg; 82%). 1H NMR: (DMSO-d6, 400 MHz) δ 8.25 (1H, t, J=1.7 Hz), 8.18-8.12 (2H, m), 7.85 (1H, t, J=7.9 Hz), 7.63 (2H, br s). LC/MS (Method C): 181 (M+H)+. HPLC (Method E) Rt 2.42 min (Purity: 99.3%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([OH:14])=[CH:6][CH:5]=1.[O:15]([CH2:22][CH2:23][CH2:24]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([O:14][CH2:24][CH2:23][CH2:22][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: BrCCCOc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1nc(Br)ccc1OCCCOc1ccccc1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
Sodium hydride (60% in mineral oil, 172 mg, 4.53 mmol) was added to a mixture of methyl 6-bromo-3-hydroxypicolinate (26B) (1.0 g, 4.31 mmol) and 3-phenoxypropyl bromide (927 mg, 4.31 mmol) in DMA (20 mL) at rt. The mixture was heated to 100° C. for 1.75 hours, cooled, diluted with 10% citric acid and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-75:25, to provide 1.35 g (86%) of the desired product methyl 6-bromo-3-(3-phenoxypropoxy)picolinate (26C): 1H NMR (300 MHz, CDCl3) δ 7.52 (1H, d), 7.27 (2H, m), 6.92 (2H, m), 4.25 (2H, t), 4.19 (2H, t), 3.92 (3H, s), 2.30 (2H, t).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=O)[C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.[CH3:39][O:40][CH2:41][CH2:42][NH2:43].Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.O.O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25](=[O:27])[NH:43][CH2:42][CH2:41][O:40][CH3:39])[C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3c(C(=O)O)cccc3[nH]2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COCCNC(=O)c1cccc2[nH]c(NCC3CCN(C(=O)OC(C)(C)C)CC3)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After suspending 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid (1.20 g, 3.20 mmol) in a mixed solvent of dimethylformamide and tetrahydrofuran (1:1, 20 ml), 1-hydroxybenzotriazole monohydrate (737 mg, 4.81 mmol) and 2-methoxyethylamine (0.42 ml, 4.8 mmol) were added. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.90 g, 6.40 mmol) was further added, and then the mixture was stirred at room temperature for 4 hours. Water (100 ml) was added to the reaction mixture, extraction was preferred with ethyl acetate (150 ml×3 times), and the organic layer was washed with saturated brine (100 ml) and then dried over anhydrous magnesium sulfate. The residue obtained by concentrating this under reduced pressure was purified by silica gel column chromatography (ethyl acetate/methanol=30/1) to obtain 4-{[4-(2-methoxy-ethylcarbamoyl)-1H-benzimidazol-2-ylamino)-methyl}-piperidine-1-carboxylic acid tert-butyl ester. The compound was identified by LC-MS.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][C@@H:14]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:13][C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: F[C@@H]1CCNC1

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.356 g, 1.87 mmol), tert-butyl (3R)-3-fluoropyrrolidine-1-carboxylate (See Intermediate50) (0.353 g, 1.87 mmol) and ethanol (2 mL) to give the title compound as a white solid (0.478 g): MS (m/e): 90 (M+1).
Reaction SMILES: O.[OH-].[Na+].[NH2:4][CH2:5][C:6]([OH:8])=[O:7].[N+](C1C=CC=CC=1)([O-])=O.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].Cl>C(#N)C>[C:18]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Solvent: CC#N
Product: C=C(C)C(=O)NCC(=O)O
Temperature: -20 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To 400 ml of water containing 80 g (2.0 mol) of sodium hydroxide dissolved, were added 150 g (2.0 mol) of glycine and 4 ml of nitrobenzene. To the mixture, there were simultaneously added 200 ml of an aqueous solution containing 96 g (2.4 mol) of sodium hydroxide and 230 g (2.2 mol) of methacrylic chloride under cooling (at -20° C.) with stirring over a period of about 2 hours. After adding 800 ml of acetonitrile and 160 ml of concentrated hydrochloric acid, the organic layer was separated. The solvent was distilled off under a reduced pressure and the crystals thus deposited were collected by filtration and recrystallized from ethyl acetate to obtain 184 g (64.3% yield) of α-methacryloylaminoacetic acid.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:33]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(Nc5ccccc5CN(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 3-(4-methylpiperazin-1-yl)aniline (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.033 g, 31%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.98 (d, J=6.5 Hz, 1H), 7.45-7.39 (m, 2H), 7.35 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.18-7.11 (m, 3H), 6.96 (s, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.77 (s, 1H), 6.70 (t, J=7.0 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 4.36 (s, 2H), 3.28-3.23 (m, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.