Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC(C)(C)C)=O)[CH2:13][C:14]([F:22])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]=1[F:30])[CH3:2].Cl>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:22])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]=1[F:30])[CH3:2]
Reactant: CCOC(=O)Cc1ccnc(N(CC(F)(F)c2ccccn2)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccnc(NCC(F)(F)c2ccccn2)c1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Through a 0° C. solution of 0.218 g (0.496 mmol) ethyl {2-[(tert-butoxycarbonyl)(2,2-difluoro-2-pyridin-2-ylethyl)amino]-3-fluoropyridin-4-yl}acetate 29-1 in 10 mL EtOAc was passed a steady stream of HCl gas for 10 min. The reaction was stirred at 0° C. for 1.5 h and then at room temperature for 10 min. The reaction mixture was then flushed with N2 and poured onto 150 mL EtOAc/50 mL 2M NaOH/7 mL conc NaOH. The layers were mixed and then separated. The aqueous layer was back extracted with 50 mL EtOAc. The combined organics were washed w/50 mL water and 50 mL brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by automated flash chromatography (40 g silica cartridge, linear gradient 0-50% EtOAc/hexane over 30 min, 30 mL/min flow rate) gave ethyl {2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-3-fluoropyridin-4-yl}acetate 29-2. 1H NMR (CDCl3, 400 MHz) δ8.663 (d, 1H, J=4.67 Hz, ArH); 7.829-7.790 (m, 2H, ArH); 7.693 (d, 1H, J=7.14 Hz, ArH); 7.377 (t, 1H, J=6.14 Hz, ArH); 6.489 (t, 1H, J=4.99 Hz, ArH); 4.492-4.405 (m, 2H, CH2); 4.199-4.145 (m, 2H, CH2); 3.585 (s, 2H, CH2); 1.276-1.237 (m, 3H, CH3); MS (Electrospray): m/z 340.1 (M+H).
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([F:9])[CH3:8])([O:5][CH3:6])=[O:4].C(OC(=O)[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:28][C:27]=1[NH2:37])(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:6][O:5][P:3]([C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:37][C:27]2[CH:28]=[C:29]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH:30]=[CH:31][C:26]=2[NH2:25])=[CH:17][CH:18]=1)([F:9])[CH3:8])(=[O:4])[O:2][CH3:1]
Reactant: COP(=O)(OC)C(C)(F)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COP(=O)(OC)C(C)(F)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[1-(Dimethoxy-phosphoryl)-1-fluoro-ethyl]-benzoic acid (50 mg, 0.18 mmol), (2-Amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (63 mg, 0.22 mmol), BOP (96 mg, 0.22 mmol), and DIPEA (70 mg, 0.54 mmol) were combined and diluted with DMF (0.72 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, and concentrated in vacuo. The residue was diluted with 5:1 CH2Cl2:TFA. The resulting solution was stirred at ambient temperature for 1 h then concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) 10.15 (s, 1H), 8.05 (d, J=9.0 Hz, 2H), 7.56-7.62 (m, 3H), 7.43-7.48 (m, 2H), 7.37 (d, J=3.5 Hz, 1H), 7.06-7.09 (m, 2H), 3.72 (d, J=10.8 Hz, 3H), 3.57 (d, J=10.8 Hz, 3H), 1.86-1.96 (m, 3H). MS: cal'd 449 (MH+), exp 449 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=[O:8].C(N(CC)CC)C.[N+:16]([CH3:19])([O-:18])=[O:17]>>[N+:16]([CH2:19][CH:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)[OH:8])([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cnccn1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])CC(O)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a round bottom flask was added 2-pyrazinecarboxaldehyde (770 mg, 7.12 mmol) in 10 mL of nitromethane, followed by the addition of triethylamine (721 mg, 7.12 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a flash chromatography column. The column was eluted with 0–5% MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 1124 mg (93.3%) of 2-nitro-1-pyrazin-2-yl-ethanol. (TLC: Rf=0.2, 5% MeOH/CH2Cl2, UV).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C:14]([O-:16])=[O:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Yield: 91.8 %

Procedure:
A solution of (S)-β-[[(phenylmethoxy)carbonyl]amino]-benzenepropanoate (1.60 g, 5.11 mmol), 1 M NaOH (25 mL) and THF (25 mL) is stirred 18 hours at ambient temperature. The reaction is concentrated in vacuo to remove THF, the residue diluted with 30 mL H2O, and washed with (3×25 mL) Et2O. The aqueous phase is brought to pH=3 with concentration. HCl and the resulting precipitate collected and dried to afford 1.40 g (4.69 mmol, 92%) product as a white solid. mp 135° C.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N)(OC(C)(C)C)=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:17])[CH3:2]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=CCc1ccccc1C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccccc1C1CCNCC1

Procedure:
A solution of 4-(2-oxoethylphenyl)-piperidine-N-Boc-amine was stirred in a solution of DCM (3 mL) and trifluoroacetic acid (1 mL) for 1 h, concentrated under reduced pressure, residual solvent was coevaporated twice from methanol, and dried under high vacuum to provide the N-deprotected 4-(2-acetylphenyl)piperidine. Using standard reductive amination conditions 4-(2-acetylphenyl)piperidine was reacted with N-[2-(S)-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-1-naphthamide and converted to the citrate salt. MS m/z 612 (M+H).
Reaction SMILES: C1C[O:4][CH2:3]C1.[Li]C(CC)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=1.Cl>C1CCCCC1.CN(C=O)C>[F:11][C:12]1[CH:13]=[C:14]([CH3:22])[C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][C:17]=1[CH:3]=[O:4]
Reactant: Cc1cc(F)ccc1C(F)(F)F
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: Cc1cc(F)c(C=O)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. flask containing THF (7 mL) was added s-BuLi (10 mL of a 1.4 M solution in cyclohexane, 14.0 mmol). To this −78° C. solution was added a solution of 4-fluoro-2-methyl-1-(trifluoromethyl)benzene (2.0 g, 11.23 mmol) in heptanes (7 mL) over 20 minutes. The reaction was stirred at −78° C., for 1 hour and then DMF (1.5 mL) was added. Next, 1N HCl (30 mL) was added, and the reaction was warmed to room temperature and stirred for 10 minutes. The mixture was extracted with hexanes (75 mL) and the organic layer was washed with water and brine (20 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel afforded 2-fluoro-4-methyl-5-(trifluoromethyl)benzaldehyde. Rf=0.44 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 10.31 (s, 1H), 8.14 (d, J=6.6 Hz, 1H), 7.13 (d, J=10.5 Hz, 1H), 2.56 (d, J=1.3 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[N:11][C:12]2[CH:31]=[CH:30][C:15]([C:16]([NH:18][C:19]([NH:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:17])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>O1CCCC1.CO>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:18][C:19]([NH:21][NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[O:20])=[O:17])=[CH:30][CH:31]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=Nc2ccc(C(=O)NC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Nc1nc(CNc2ccc(C(=O)NC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
tert-Butyl 2-{[4-({[2-(acetylamino)-1,3-thiazol-4-yl]methylidene}amino)benzoyl]carbamoyl}hydrazinecarboxylate (778.5 mg, 1.800 mmol) was dissolved in a mixed solvent of anhydrous tetrahydrofuran (18 ml) and anhydrous methanol (9 ml), and the mixture was cooled to 0° C. Sodium borohydride (68.1 mg, 1.80 mmol) was added and the mixture was stirred at room temperature for 30 min. Acetic acid (0.22 ml, 3.85 mmol) was added and the mixture was stirred for 15 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 40 g, dichloromethane:methanol=20:1→15:1). The pure fractions were concentrated under reduced pressure, ethyl acetate (30 ml) and tert-butyl methyl ether (10 ml) were added to the residue, and the resulting solid was collected by filtration and dried under reduced pressure to give tert-butyl 2-{[4-({[2-(acetylamino)-1,3-thiazol-4-yl]methyl}amino)benzoyl]carbamoyl}hydrazinecarboxylate (653.1 mg, 1.503 mmol, yield 83.5%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 8.2 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (300.2 mg) and ethyl 4-aminophenylacetate hydrochloride (202.2 mg) were condensed in THF (5 ml) in the presence of triethylamine (422.4 μl) and pivaloyl chloride (153.9 μl), and then the resulting crude product was recrystallized from ethanol to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (35.1 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:11]([CH2:21][C:22]2[N:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][Si](C=[N+]=[N-])(C)C.CCCCCC>C1C=CC=CC=1.CO>[CH3:33][O:25][C:24](=[O:26])[C:23]1[CH:27]=[CH:28][CH:29]=[N:30][C:22]=1[CH2:21][C@@H:11]1[O:10][C:9]([CH3:32])([CH3:31])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:12]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)C(Cc2ncccc2C(=O)O)OC1(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cccnc1C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(R)-3-tert-butoxycarbonyl-4-(2-fluoro-benzyl)-2,2-dimethyl-oxazolidin-5-ylmethyl]-nicotinic acid (11 g, 25 mmol) in 200 mL of benzene and 30 mL of methanol is added a 2M solution of trimethylsilyl-diazomethane in hexane (16 mL, 32 mmol). The reaction is allowed to stir for 1 hour at RT after which time the solvent is removed under reduced pressure. Purification of the resultant residue by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.FC1C=CC(C#N)=C(C(F)(F)F)C=1C=O.[BH4-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[C:9]([CH2:10][OH:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:3]=1
Reactant: N#Cc1cc(C=O)c(F)cc1C(F)(F)F
Agent: N#Cc1ccc(F)c(C=O)c1C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(CO)c(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
To a solution (15 mL) of a mixture (1.01 g) of 4-fluoro-5-formyl-2-(trifluoromethyl)benzonitrile and 4-fluoro-3-formyl-2-(trifluoromethyl)benzonitrile (3:1) in tetrahydrofuran was added sodium borohydride (400 mg) at 0° C., and the mixture was stirred at room temperature for 12 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=5:1→1:4) to give the title compound as a yellow oil (yield: 456 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:26]=[N:27][C:28](F)=[CH:29][C:30]=3[CH3:31])=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1.O>CN(C)C=O>[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[N:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCC4=O)cc3C)CC2)c(C)c1
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
Pyrrolidin-2-one (322 mg) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (159 mg) was added, and the mixture was stirred for 30 min. To the reaction mixture was further added [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (620 mg) described in Preparation Example 146, and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:55])([F:54])[C:27]1[N:31]2[N:32]=[C:33]([N:36]3[CH2:41][CH2:40][CH:39]([C:42]4[C:50]5[C:45](=[CH:46][CH:47]=[C:48]([C:51]([OH:53])=O)[CH:49]=5)[NH:44][CH:43]=4)[CH2:38][CH2:37]3)[CH:34]=[CH:35][C:30]2=[N:29][N:28]=1.[CH3:56][NH:57][CH2:58][CH2:59][OH:60].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:60][CH2:59][CH2:58][N:57]([CH3:56])[C:51]([C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH:43]=[C:42]2[CH:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:34]=[CH:35][C:30]3[N:31]([C:27]([C:26]([F:25])([F:54])[F:55])=[N:28][N:29]=3)[N:32]=2)[CH2:41][CH2:40]1)=[O:53]
Reactant: O=C(O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Reactant: CNCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
HATU (139 mg, 0.37 mmol) was added portionwise at ambient temperature to a stirred mixture of 3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxylic acid (150 mg, 0.35 mmol), 2-(methylamino)ethanol (0.034 mL, 0.42 mmol) and DIPEA (0.073 mL, 0.42 mmol) in DMF (2.0 mL). The resulting solution was stirred for 2 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(2-hydroxyethyl)-N-methyl-3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxamide (155 mg, 91%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27]OS(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:27][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Product: COC(=O)CCCCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(7-methoxycarbonylheptyl)propanamide (152.2 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1yl)-N-(7-methoxycarbonylheptyl)propanamide (53.4 ml) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=1.[OH-].[Na+]>C(O)(=O)C>[NH2:3][C:4]1[N:9]=[C:8]([Cl:1])[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: CSc1nc(N)nc(C(F)(F)F)n1
Reactant: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc(Cl)nc(C(F)(F)F)n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Chlorine gas was passed into a solution of 21 g of 2-amino-4-methylthio-6-trifluoromethyl-1,3,5-triazine in 0.2 l glacial acetic acid at 20 to 25° C. (15 min). The reaction mixture was stirred for 30 min at approx. 20° C., sprayed for 1 hour with nitrogen gas at room temperature, poured into 1 l of ice-cold aqueous solution of 70 g of sodium hydroxide and stirred for 5 min. After extraction with ethyl acetate, the organic phase was washed with water and dried over magnesium sulfate, and the solvent was removed in vacuo. The crude product was purified by stirring in heptane. After filtration with suction and drying, 12 g (60%) of 2-amino-4-chloro-6-trifluoromethyl-1,3,5-triazine were obtained as a white powder (m.p. 109° C.); 1H NMR (CDCl3): δ=6.4 (s br., 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:12][B-:13]([F:16])([F:15])[F:14].[CH3:17][O+](C)C>C(Cl)Cl>[F:12][B-:13]([F:16])([F:15])[F:14].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N+:3]=1[CH3:17]
Reactant: C[O+](C)C
Reactant: Brc1nccc2ccccc12
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[n+]1ccc2ccccc2c1Br

Procedure:
The starting material was prepared by reaction of 1-bromoisoquinoline with trimethyloxonium tetrafluoroborate in CH2Cl2 to give 1-bromo-2-methylisoquinolinium tetrafluoroborate, m.p. 162°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([OH:19])([CH2:15][C:16](O)=[O:17])[CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([OH:19])([CH2:15][CH2:16][OH:17])[CH2:8]2
Reactant: COc1ccc(OC)c2c1CCC(O)(CC(=O)O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(OC)c2c1CCC(O)(CCO)C2

Procedure:
15.5 g of 5,8-dimethoxy-1,2,3,4-tetrahydro-2-hydroxy-2-naphthaleneacetic acid in 150 ml of tetrahydrofuran were added dropwise within 15 minutes to 3.32 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The reaction mixture was heated to reflux for 1 hour and then cooled. After the dropwise addition of 15 ml of ethyl acetate and 20 ml of water the suspension was filtered and the filtrate was concentrated. The product was purified by column chromatography (silica gel, chloroform/methanol 30:1). There was obtained 5,8-dimethoxy-1,2,3,4-tetrahydro-2-hydroxy-2-naphthaleneethanol, m.p. 121°-122°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)Cc1ccc(Br)cc1
Yield: 57.9 %

Procedure:
A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv), dimethylamine (13.20 g, 96.80 mmol, 1.20 equiv, 33%) and potassium carbonate (13.36 g, 96.81 mmol, 1.20 equiv) in ethanol (200 mL) was stirred overnight at 50° C. The solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in 200 mL of water and extracted with 3×200 mL of dichloromethane. The combined organic layer was washed with 3×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (20:1) to give 10 g (58%) of (4-bromophenyl)-N,N-dimethylmethanamine as a yellow oil. LC-MS: (ES, m/z): 255 [M+CH3CN+H]+, 214 [M+H]+, 169.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1c[nH]c2ccc(Cl)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a flask, (E)-3-(5-chloro-1H-indol-3-yl)-acrylic acid methyl ester (8, 3.4 g, 0.014 mol) and 10% palladium on carbon were combined and 140 mL of ethyl acetate was added. Vacuum was applied and the flask was back filled with hydrogen, repeated application of vacuum and hydrogen back fill for total of three times. The reaction was capped with a hydrogen filled balloon and the reaction stirred overnight at room temperature. TLC (20% ethyl acetatethexane) indicated absence of starting material and a major new spot. The reaction was filtered through celite and the filter rinsed generously with a total of 250 mL of ethyl acetate. The yellow filtrate solution was roto-evaporated to near dryness, silica was added, and the solvent fully removed. Column chromatography was performed, eluting with 2 to 30% ethyl acetate/hexane, then flushing with 40% ethyl acetate/hexane to provide the desired compound. 1H NMR consistent with structure.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:18])[N:8]([CH3:17])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1)[CH3:3].[O-:19][C:20]#[N:21].[Na+].FC(F)(F)C(O)=O.O>C1C=CC=CC=1>[NH2:21][C:20]([O:1][CH:2]([C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:18])[N:8]([CH3:17])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1)[CH3:3])=[O:19]
Reactant: N#C[O-]
Reactant: CC(O)c1cc2c3ccccc3n(C)c(=O)n2n1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(OC(N)=O)c1cc2c3ccccc3n(C)c(=O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3.7 g (0.0172 mole) of 2-(1-hydroxyethyl)-6-methylpyrazolo[1,5-c]quinazolin-5(6H)-one in 30 ml of benzene there is added 2.6 g (0.036 mole) of solid, 90% sodium cyanate followed by the dropwise addition of 3.1 ml (0.041 mole) of trifluoroacetic acid. The reaction mixture is stirred on a magnetic stirrer at approximately 120 revolutions per minute for 2 hours at room temperature. By the end of this time a gum separates. The reaction mixture is subsequently treated with 15 ml of water with increased stirring speed after which a solid (insoluble in either phase) forms. This is filtered, washed with water and air dried to give 2.9 g (60% direct yield), m.p. 216°-221°. The solid is twice crystallized from chloroform-methanol (1:1) to give 2.0 g of analytically pure material, m.p. 250°-252°.